Propanolamine derivatives

ABSTRACT

Propanolamine derivatives represented by the following formula (I):                    
     These derivatives may be β 3  agonists and exert sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic and anti-urinary incontinence and anti-pollakiuria activities. Pharmaceutical compositions containing such propanolamine derivatives, methods for the prevention and/or treatment diseases using these propanolamine derivatives, and processes for their preparation are also described.

TECHNICAL FIELD

This invention relates to new propanolamine derivatives which is the β₃adrenergic receptor agonist and salts thereof which are useful as amedicament.

DISCLOSURE OF INVENTION

This invention relates to new propanolamine derivatives which is the β₃adrenergic receptor agonist and salts thereof.

More particularly, it relates to new propanolamine derivatives and saltsthereof which have gut selective sympathomimetic, anti-ulcerous,anti-pancreatitis, lipolytic, anti-urinary incontinence andanti-pollakiuria activities, to processes for the preparation thereof,to a pharmaceutical composition comprising the same and to a method ofusing the same therapeutically in the treatment and/or prevention ofgastro-intestinal disorders caused by smooth muscle contractions inhuman beings or animals, and more particularly to a method for thetreatment and/or prevention of spasm or hyperanakinesia in case ofirritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer,enteritis, cholecystopathy, cholangitis, urinary calculus and the like;for the treatment and/or prevention of ulcer such as gastric ulcer,duodenal ulcer, peptic ulcer, ulcer caused by non steroidalanti-inflammatory drugs, or the like; for the treatment and/orprevention of dysuria such as pollakiuria, urinary incontinence or thelike in case of nervous pollakiuria, neurogenic bladder dysfunction,nocturia, unstable bladder, cystospasm, chronic cystitis, chronicprostatitis, overflow incontinence, passive incontinence, refluxincontinence, urge incontinence, urinary stress incontinence or thelike; and for the treatment and/or prevention of pancreatitis, obesity,diabetes, glycosuria, hyperlipidemia, hypertension, atherosclerosis,glaucoma, melancholia, depression and the like.

One object of this invention is to provide new and useful propanolaminederivatives and salts thereof which have gut selective sympathomimetic,anti-ulcerous, lipolytic, anti-urinary incontinence and anti-pollakiuriaactivities.

Another object of this invention is to provide processes for thepreparation of said propanolamine derivatives and salts thereof.

A further object of this invention is to provide a pharmaceuticalcomposition comprising, as an active ingredient, said propanolaminederivatives and salts thereof.

Still further object of this invention is to provide a therapeuticalmethod for the treatment and/or prevention of aforesaid diseases inhuman beings or animals, using said propanolamine derivatives and saltsthereof.

The object propanolamine derivatives of this invention are new and canbe represented by the following general formula [I]:

wherein

R¹ is aryl which may have one or more suitable substituent(s),heterocyclic group or cyclo(lower)alkyl,

R² is hydrogen or amino protective group,

R³ and R⁴ are independently hydrogen, halogen, hydroxy, amino, nitro,carboxy, protected carboxy, aryl, lower alkyl, hydroxy(lower)alkyl,amino(lower)alkyl, acyloxy(lower)alkyl, acylamino(lower)alkyl, loweralkylamino(lower)alkyl which may have one or more suitablesubstituent(s), mono or di-(lower)alkylamino, acylamino, acyl group,lower alkoxy, halo(lower)alkoxy, lower alkenyloxy, loweralkoxy(lower)alkoxy, aryloxy, cyclo(lower)alkyloxy, heterocyclicoxy,ar(lower)alkyloxy, acyloxy or acyl(lower)alkoxy,

R⁵ is hydrogen, lower alkyl, or aryl,

A is lower alkylene which may have one or more suitable substituent(s)or lower alkenylene,

X is O, S, SO, SO₂ or NH, and

m is an integer of 0 or 1.

The object compound [I] or a salt thereof can be prepared by thefollowing processes.

wherein

R¹, R², R³, R⁴, R⁵, A, X and m are each as defined above, and

R_(a) ² is amino protective group.

In the above and subsequent description of the present specification,suitable examples of the various definition to be included within thescope of the invention are explained in detail in the following.

The term “lower” is intended to mean a group having 1 to 6 carbonatom(s), unless otherwise provided.

The preferable number of the “one or more” in the term of “one or moresuitable substituent(s)” may be 1 to 4.

Suitable example of “halogen” may be fluoro, chloro, bromo, iodo, andthe like.

Suitable example of “lower alkyl” may include straight or branched onehaving 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylpentyl,tert-pentyl, neo-pentyl, hexyl, isohexyl and the like.

Suitable example of “higher alkyl” may include straight or branched onehaving 7 to 20 carbon atoms, such as heptyl, octyl, 3,5-dimethyloctyl,3,7-dimethyloctyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl,pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, and thelike.

Suitable “lower alkoxy” and “lower alkoxy” moiety may be a straight orbranched one such as methoxy, ethoxy, propoxy, isopropoxy,1-ethylpropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy,neopentyloxy, tert-pentyloxy, hexyloxy, and the like.

Suitable example of “aryl” and “ar” moiety may include phenyl which mayhave lower alkyl (e.g., phenyl, mesityl, tolyl, etc.), naphthyl,anthryl, and the like, in which the preferred one may be phenyl andnaphthyl.

Suitable example of “aroyl” moiety may include benzoyl, toluoyl,naphthoyl, anthrylcarbonyl, and the like, in which the preferred one maybe benzoyl and naphthoyl.

Suitable example of “protected carboxy” may be a conventional protectinggroup such as an esterified carboxy group, or the like, and concreteexamples of the ester moiety in said esterified carboxy group may be theones such as lower alkyl ester [e.g. methyl ester, ethyl ester, propylester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester,pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.] which mayhave suitable substituent(s), for example, lower alkanoyloxy(lower)alkylester [e.g. acetoxymethyl ester, propionyloxymethyl ester,butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester,1-acetoxyethyl ester, 1-propionyloxyethyl ester, pivaloyloxyethyl ester,2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc.], loweralkanesulfonyl(lower)alkyl ester [e.g. 2-mesylethyl ester, etc.] ormono(or di or tri)halo(lower)alkyl ester [e.g. 2-iodoethyl ester,2,2,2-trichloroethyl ester, etc.];

higher alkyl ester [e.g. heptyl ester, octyl ester, 3,5-dimethyloctylester, 3,7-dimethyloctyl ester, nonyl ester, decyl ester, undecyl ester,dodecyl ester, tridecyl ester, tetradecyl ester, pentadecyl ester,hexadecyl ester, heptadecyl ester, octadecyl ester, nonadecyl ester,adamantyl ester, etc.];

lower alkenyl ester [e.g. (C₂-C₆)alkenyl ester (e.g. vinyl ester, allylester, etc.)];

lower alkynyl ester [e.g. (C₂-C₆)alkynyl ester (e.g. ethynyl ester,propynyl ester, etc.)];

ar(lower)alkyl ester which may have one or more suitable substituent(s)[e.g. phenyl(lower)alkyl ester which may have 1 to 4 lower alkoxy,halogen, nitro, hydroxy, lower alkyl, phenyl, or halo(lower)alkyl (e.g.benzyl ester, 4-methoxybenzyl ester, 4-chlorobenzyl ester, 4-nitrobenzylester, phenethyl ester, trityl ester, benzhydryl ester,bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,4-hydroxy-3,5-di-tert-butylbenzyl ester, 4-trifluoromethylbenzyl ester,etc.)];

aryl ester which may have one or more suitable substituent(s) [e.g.phenyl ester which may have 1 to 4 lower alkyl, or halogen (e.g. phenylester, 4-chlorophenyl ester, tolyl ester, 4-tert-butylphenyl ester,xylyl ester, mesityl ester, cumenyl ester, etc.)];

cycloalkyloxycarbonyloxy(lower)alkyl ester which may have lower alkyl(e.g., cyclopentyloxycarbonyloxymethyl ester,cyclohexyloxycarbonyloxymethyl ester, cycloheptyloxycarbonyloxymethylester, 1-methylcyclohexyloxycarbonyloxymethyl ester, 1-(or2-)[cyclopentyloxycarbonyloxy]ethyl ester, 1-(or2-)[cyclohexyloxycarbonyloxy]ethyl ester, 1-(or2-)-[cycloheptyloxycarbonyloxy]ethyl ester, etc.), etc.];

(5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g.,(5-methyl-2-oxo-l,3-dioxol-4-yl)methyl ester,(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-propyl-2-oxo-1,3-dioxol-4-yl)methyl ester, 1-(or2-)(5-methyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or2-)(5-ethyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or2-)(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; or the like,

in which the preferred one may be lower alkyl ester, loweralkanoyloxy(lower)alkyl ester, ar(lower)alkyl ester which may have oneor more suitable substituent(s), cycloalkyloxycarbonyloxy(lower)alkylester which may have lower alkyl, higher alkyl ester, and[5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl](lower)alkyl ester;

and the more preferred one may be methyl ester, ethyl ester, isobutylester, butyl ester, pentyl ester, hexyl ester, benzyl ester,4-trifluoromethylbenzyl ester, 4-chlorobenzyl ester, adamantyl ester,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(1-cyclohexyloxycarbonyloxy)ethyl ester and pivaloyloxymethyl ester, andthe like, in which the preferred one may be (C₁-C₄)alkyl ester, and themost preferred one may be ethyl ester.

Suitable “acyl group” and “acyl” moiety may include carbamoyl,sulfamoyl, sulfinamoyl, sulfenamoyl, aliphatic acyl group and acyl groupcontaining an aromatic ring, which is referred to as aromatic acyl, orheterocyclic ring, which is referred to as heterocyclic acyl.

Suitable example of said acyl may be illustrated as follows :

carbamoyl; sulfamoyl; sulfinamoyl; sulfenamoyl; aliphatic acyl such aslower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl,2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl,heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl,tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl,octadecanoyl, nonadecanoyl, icosanoyl, etc.);

cyclo(lower)alkylcarbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.);protected carboxy such as commonly protected carboxy [e.g., esterifiedcarboxy such as lower or higher alkoxycarbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl,t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.), etc.],or the like; lower alkylcarbamoyl (e.g., methylcarbamoyl,dimethylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl,pentylcarbamoyl, hexylcarbamoyl, etc.);

lower or higher alkylsulfonyl (e.g., methylsulfonyl, dimethylsulfonyl,ethylsulfonyl, etc.); lower or higher alkoxysulfonyl (e.g.,methoxysulfonyl, ethoxysulfonyl, etc.);

di-(lower)alkoxyphosphoryl (e.g, dimethoxyphosphoryl,diethoxyphosphoryl, dipropoxyphosphoryl, dibutoxyphosphoryl,dipentyloxyphosphoryl, dihexyloxyphosphoryl, etc.), lower alkylsulfamoyl(e.g., methylsulfamoyl, dimethylsulfamoyl, ethylsulfamoyl,propylsulfamoyl, butylsulfamoyl, pentylsulfamoyl hexylsulfamoyl, etc.),

aromatic acyl such as

aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.);

ar(lower)alkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl,phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl,phenylhexanoyl, etc.), naphthyl(lower)alkanoyl (e.g., naphthylacetyl,naphthylpropanoyl, naphthylbutanoyl, etc.), etc.];

ar(lower)alkenoyl [e.g., phenyl(lower)alkenoyl (e.g., phenylpropenoyl,phenylbutenoyl, phenylmethacryloyl, phenylpentanoyl, phenylhexenoyl,etc.), naphthyl(lower)alkenoyl (e.g., naphthylpropenoyl,naphthylbutenoyl, etc.), etc.];

ar(lower)alkoxycarbonyl [e.g., phenyl(lower)alkoxycarbonyl (e.g.,benzyloxycarbonyl, etc.), etc.);

aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxcarbonyl, etc.);

aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.);

arylcarbamoyl (e.g., phenylcarbamoyl, etc.);

arylthiocarbamoyl (e.g., phenylthiocarbamoyl, etc.); arylglyoxyloyl(e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.); arylsulfonyl (e.g.,phenylsulfonyl, p-tolylsulfonyl, etc.); or the like.

heterocyclic acyl such as

heterocycliccarbonyl;

heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl,heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl,heterocyclichexanoyl, etc.);

heterocyclic(lower)alkenoyl (e.g., heterocyclicpropenoyl,heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexanoyl,etc.); heterocyclicglyoxyloyl;

or the like; and the like.

Suitable example of “heterocyclic group” and “heterocyclic” moiety mayinclude

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g.,1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s), for example, indolyl, dihydroindolyl, isoindolyl, indolinyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,benzotriazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s) for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, morpholino, sydnonyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl(e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolidinyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s), for example,thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, imidazothiadiazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom, for example, furyl,etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom, for example,tetrahydrofuran, tetrahydropyran, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom and 1 to 2 sulfuratom(s), for example, dihydrooxathiinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s), for example, benzothienyl, benzodithiinyl, etc.;

unsaturated condensed heterocyclic group containing an oxygen atom and 1to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like,and the abovementioned “heterocyclic group” and “heterocyclic” moietymay have one or more suitable substituent(s) such as amino, oxo, cyano,aryl, ar(lower)alkyl, heterocyclc group.

Suitable example of “cyclo(lower)alkyl” may include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like, in which thepreferred one may be cyclo(C₄-C₆)alkyl, and the most preferred one maybe cyclopentyl and cyclohexyl.

Suitable example of “amino protective group” moiety may be common aminoprotective group such as acyl, for example, substituted or unsubstitutedlower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.],phthaloyl, lower alkoxycarbonyl [e.g. tert-butoxycarbonyl,tert-amyloxycarbonyl, etc.], substituted or unsubstitutedaralkyloxycarbonyl [e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl,etc.], substituted or unsubstituted arenesulfonyl [e.g. benzenesulfonyl,tosyl, etc.], nitrophenylsulfenyl, ar(lower)alkyl [e.g. trityl, benzyl,etc.], and the like, in which preferable one may be lower alkoxycarbonyland phenyl(lower)alkyl, and the most preferred one may betert-butoxycarbonyl and benzyl.

Suitable example of “aryl” moiety in the term of “aryl which may haveone or more suitable substituent(s)” in R¹ can be referred toaforementioned “aryl”, in which the preferred one may be phenyl.

Suitable example of “suitable substituent(s)” moiety in the term of“aryl which may have one or more suitable substituent(s)” may includehydroxy, halogen, lower alkylsulfonylamino, lower alkanoylamino, and thelike.

Suitable example of “lower alkylsulfonylamino” may includemethylsulfonylamino, ethylsulfonylamino, propylsulfonylamino,butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino, and thelike, in which the preferred one may be (C₁-C₄)alkylsulfonylamino, andthe most preferred one may be methylsulfonylamino.

Suitable example of “lower alkanoylamino” may include formylamino,acetylamino, propanoylamino, butanoylamino, 2-methylpropanoylamino,pentanoylamino, hexanoylamino, and the like, in which the preferred onemay be (C₁-C₄)-alkanoylamino, and the most preferred one may beacetylamino.

Suitable example of “heterocyclic group” in R¹ can be referred toaforementioned “heterocyclic group”, in which the preferred one may beunsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4nitrogen atom(s) which may have one or more suitable substituent(s), andunsaturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s) which may have one or more suitable substituent(s), and the mostpreferred one may be pyridyl, aminopyridyl, indolyl and benzimidazolone.

Suitable example of “cyclo(lower)alkyl” in R¹ can be referred toaforementioned “cyclo(lower)alkyl”, in which the preferred one may becyclo(C₄-C₆)alkyl, and the most preferred one may be cyclopentyl.

Suitable example of “mono or di lower alkylamino” may includemethylamino, dimethylamino, ethylamino, diethylamino, propylamino,isopropylamino, butylamino, methylbutylamino, sec-butylamino,1-methylpentylamino, ethylpentylamino, hexylamino, and the like, inwhich the preferred one may be mono or di(C₁-₄)alkylamino, and the mostpreferred one may be dimethylamino.

Suitable example of “hydroxy(lower)alkyl” may include hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl,and the like, in which the preferred one may be hydroxy(C₁-C₄)alkyl, andthe most preferred one may be hydroxymethyl.

Suitable example of “amino(lower)alkyl” may include aminomethyl,aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, and thelike, in which the preferred one may be amino(C₁-C₄)alkyl, and the mostpreferred one may be aminomethyl.

Suitable example of “acyl” moiety in the term of “acyloxy(lower)alkyl”can be referred to aforementioned “acyl”, in which the preferred one maybe lower alkanoyl, and the most preferred one may be acetyl.

Suitable example of “acyloxy(lower)alkyl” may include loweralkanoyloxy(lower)alkyl, in which the preferred one may be(C₁-C₄)alkanoyloxy(C₁-C₄)alkyl, and the most preferred one may beacetyloxymethyl.

Suitable example of “acyl” moiety in the term of “acylamino(lower)alkyl”can be referred to aforementioned “acyl”, in which the preferred one maybe lower alkanoyl, aroyl, carbamoyl, lower alkylcarbamoyl, loweralkylsulfonyl, and arylsulfonyl.

Suitable example of “acylamino(lower)alkyl” may include loweralkanoylamino(lower)alkyl, aroylamino(lower)alkyl,carbamoylamino(lower)alkyl, lower alkylcarbamoylamino(lower)alkyl, loweralkylsulfonylamino(lower)alkyl, arylsulfonylamino(lower)alkyl and thelike, in which the preferred one may be(C₁-C₄)alkanoylamino(C₁-C₄)alkyl, benzoylamino(C₁-C₄)alkyl,carbamoylamino(C₁-C₄)alkyl, (C₁-C₄)alkylsulfonylamino(C₁-C₄)alkyl andphenylsulfonylamino(C₁-C₄)alkyl, and the most referred one may beacetylaminomethyl, benzoylaminomethyl, carbamoylaminomethyl,butylcarbamoylaminomethyl, methylsulfonylaminomethyl andphenylsulfonylaminomethyl.

Suitable example of “suitable substituent” moiety in the term of “loweralkylamino(lower)alkyl which may have one or more suitablesubstituent(s)” may include lower alkyl and carboxy, in which thepreferred one may be methyl and carboxy.

Suitable example of “lower alkylamino(lower)alkyl which may have one ormore suitable substituent(s)” may includedi(lower)alkylamino(lower)alkyl, carboxy(lower)alkylamino(lower)alkyl,and the like, in which the preferred one may bedi(C₁-C₄)alkylamino(C₁-C₄)alkyl andcarboxy(C₁-C₄)-alkylamino(C₁-C₄)alkyl, and the most preferred one may bedimethylaminomethyl and carboxyethylaminomethyl.

Suitable example of “acyl” moiety in the term of “acylamino” can bereferred to aforementioned “acyl” moiety, in which the preferred one maybe lower alkanoyl, aroyl, lower alkoxycarbonyl, aryloxycarbonyl, loweralkylsulfonyl, phenylsulfonyl, sulfamoyl, lower alkylsulfamoyl, and themost preferred one may be acetyl, benzoyl, methoxycarbonyl,phenoxycarbonyl, methylsulfonyl, phenylsulfonyl, sulfamoyl anddimethylsulfamoyl.

Suitable example of “acylamino” may be acetylamino, benzoylamino,methoxycarbonylamino, phenoxycarbonylamino, methylsulfonylamino,phenylsulfonylamino, sulfamoylamino and dimethylsulfamoylamino.

Suitable example of “acyl group” can be referred to aforementioned “acylgroup”, in which the preferred one may be carbamoyl, loweralkylcarbamoyl, arylcarbamoyl, and the most preferred one may becarbamoy, methylcarbamoyl, dimethylcarbamoyl and phenylcarbamoyl.

Suitable example of “lower. alkoxy” can be referred to aforementioned“lower alkoxy”, in which the preferred one may be methoxy, ethoxy,propoxy, isopropoxy and benzyloxy.

Suitable example of “halo(lower)alkoxy” may be fluoro(lower)alkoxy,chloro(lower)alkoxy, bromo(lower)alkoxy, iodo(lower)alkoxy, and thelike, in which the preferred one may be fluoro(C₁-C₄)alkoxy,chloro(C₁-C₄)alkoxy, bromo(C₁-C₄)alkoxy, iodo(C₁-C₄)alkoxy, and the mostpreferred one may be fluoromethoxy.

Suitable example of “lower alkenyloxy” may include vinyloxy, 1-(or2-)propenyloxy, 1-(or 2- or 3-)butenyloxy, 1-(or 2- or 3- or4-)pentenyloxy, 1-(or 2- or 3- or 4- or 5-)hexenyloxy, and the like, inwhich the preferred one may be (C₂-C₄)alkenyloxy, and the most preferredone may be 2-propenyloxy.

Suitable example of “lower alkoxy(lower)alkoxy” may includemethoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxypropoxy,ethoxyethoxy, propoxymethoxy, butoxymethoxy, pentyloxymethoxy,hexyloxymethoxy, hexyloxyethoxy, and the like, in which the preferredone may be (C₁-C₄)alkoxy-(C₁-C₄)alkoxy, and the most preferred one maybe methoxyethoxy.

Suitable example of “aryloxy” may include phenoxy, mesityloxy, tolyloxy,naphthyloxy, anthryloxy, and the like, in which the preferred one may bephenoxy.

Suitable example of “cyclo(lower)alkyloxy” may include cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like, in which thepreferred one may be cyclopentyloxy.

Suitable example of “heterocyclic” moiety in the term of“heterocyclicoxy” can be referred to aforementioned “heterocyclic”moiety, in which the preferred one may be unsaturated 3 to 8-memberedheteromonocyclic group containing 1 to 4 nitrogen atoms(s) which mayhave a suitable substituent, and the most preferred one may be pyridylhaving cyano.

Suitable example of “heterocyclicoxy” may be pyridyloxy having cyano.

Suitable example of “ar(lower)alkyloxy” may includephenyl(lower)alkyloxy, mesityl(lower)alkyloxy, tolyl(lower)alkyloxy,naphthyl(lower)alkyloxy, anthryl(lower)alkyloxy, and the like, in whichthe preferred one may be phenyl(C₁-C₄)alkyloxy, and the most preferredone may be benzyloxy and phenetyloxy.

Suitable example of “acyl” moiety in the term of “acyloxy” can bereferred to aforementioned “acyl” moiety, in which the preferred one maybe carbamoyl and mono or di-lower alkylsulfamoyl, and the most preferredone may be carbamoyl and dimethylsulfamoyl.

Suitable example of “acyloxy” may be carbamoyloxy and mono or di loweralkylsulfamoyloxy and the most preferred one may be carbamoyloxy anddimethylsulfamoyloxy.

Suitable example of “lower alkoxy” moiety in the term of“acyl(lower)alkoxy” can be referred to aforementioned “lower alkoxy”, inwhich the preferred one may be (C₁-C₄)alkoxy, and the most preferred onemay be methoxy.

Suitable example of “acyl” moiety in the term of “acyl(lower)alkoxy” mayinclude the aforementioned “acyl” moiety; lower alkylcarbamoyl which mayhave one or more suitable substituent(s) selected from the groupconsisting of hydroxy, lower alkoxy, lower alkyl, ar(lower)alkyl,protected carboxy, carboxy, mono or di lower alkylamino, loweralkylthio, halo(lower)alkyl, aryl which may have one or more suitablesubstituent(s), and heterocyclic group; arylcarbamoyl which may have oneor more suitable substituent(s) selected from the group consisting oflower alkyl, higher alkyl, halogen, halo(lower)alkyl, mono or di-loweralkylamino, lower alkoxy, halo(lower)alkoxy and nitro;heterocycliccarbamoyl which may have one or more suitable substituent(s)selected from the group consisting of ar(lower)alkyl, aryl andheterocyclic(lower)alkyl which may be substituted with heterocyclicgroup; heterocycliccarbonyl which may have one or more suitablesubstituent(s) selected from the group consisting of ar(lower)alkyl andheterocyclic group which may be substituted with one or more suitablesubstituent(s); cyclo(lower)alkylcarbamoyl;guanidinocarbonyl; and thelike.

Suitable example of “lower alkylcarbamoyl” may include methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl,1-methylbutylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl,tert-butylcarbamoyl, pentylcarbamoyl, isopentylcarbamoyl,tert-pentylcarbamoyl, 1-methylpentylcarbamoyl, neopentylcarbamoyl,hexylcarbamoyl, isohexylcarbamoyl, and the like, in which the preferredone may be methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,butylcarbamoyl, sec-butylcarbamoyl, isobutylcarbamoyl,1-methylbutylcarbamoyl, and hexylcarbamoyl.

Suitable example of “lower alkoxy” in the suitable substituent(s) of theterm “lower alkylcarbamoyl which may have one or more suitablesubstituent(s)” can be referred to aforementioned “lower alkoxy”, inwhich the preferred one may be (C₁-C₄)alkoxy, and the most preferred onemay be methoxy, ethoxy and propoxy.

Suitable example of “lower alkyl” in the suitable substituent(s) of theterm “lower alkylcarbamoyl which may nave one or more suitablesubstituent(s)” can be referred to aforementioned “lower alkyl”, inwhich the preferred one may be (C₁-C₄)alkyl, and the most preferred onemay be methyl and ethyl.

Suitable example of “ar(lower)alkyl” in the suitable substituent(s) ofthe term “lower alkylcarbamoyl which may have one or more suitablesubstituent(s)” may include “mono- or di- or tri-phenyl(lower)alkyl”such as benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl,phenylhexyl, benzhydryl, trityl, and the like, in which the preferredone may be benzyl.

Suitable example of “protected carboxy” in the suitable substituent(s)of the term “lower alkylcarbamoyl which may have one or more suitablesubstituent(s)” can be referred to aforementioned “protected carboxy”,in which the preferred one may be (C₁-C₄)alkyl ester, and the mostpreferred one may be ethyl ester.

Suitable example of “mono or di-lower alkylamino” in the suitablesubstituent(s) of the term “lower alkylcarbamoyl which may have one ormore suitable substituent(s)” may include methylamino, dimethylamino,ethylamino, diethylamino, propylamino, isopropylamino, butylamino,isobutylamino, sec-butylamino, tert-butylamino, pentylamino,isopentylamino, tert-pentylamino, 1-methylpentylamino, neopentylamino,hexylamino, isohexylamino, and the like, in which the preferred one maybe di(C₁-C₄)alkylamino, and the most preferred one may be dimethylaminoand diethylamino.

Suitable example of “lower alkylthio” in the suitable substituent(s) ofthe term “lower alkylcarbamoyl which may have one or more suitablesubstituent(s)” may include methylthio, ethylthio, propylthio,butylthio, pentylthio, and the like, in which the preferred one may be(C₁-C₄)alkylthio, and the most preferred one may be methylthio.

Suitable example of “halo(lower)alkyl” in the suitable substituent(s) ofthe term “lower alkylcarbamoyl which may have one or more suitablesubstituent(s)” may include tri-halo(lower)alkyl such astrichloromethyl, trichloroethyl, trichloropropyl, trifluoromethyl,trifluoroethyl, trifluoropropyl, tribromomethyl, tribromoethyl, and thelike, in which the preferred one may be tri-halo(C₁-C₄)alkyl, and themost preferred one may be trifluoromethyl and trifluoroethyl.

Suitable example of “aryl” in the term of “aryl which may have one ormore suitable substituent(s)” can be referred to aforementioned “aryl”,in which the preferred one may be phenyl.

Suitable example of “suitable substituent(s)” in the term of “aryl whichmay have one or more suitable substituent(s)” may include mono ordi(lower)alkylamino(lower)alkyl (e.g., methylaminomethyl,dimethylaminomethyl, dimethylaminoethyl, diethylaminoethyl,dimethylaminopropyl, propylaminopropyl, butylaminoethyl,diethylaminopentyl, etc.), in which the preferred one may be mono ordi(C₁-C₄)alkylamino(C₁-C₄)alkyl, and the most preferred one may bedimethylaminomethyl.

Suitable example of “heterocyclic group” can be referred toaforementioned “heterocyclic group”, in which the preferred one may besaturated or unsaturated 3 to 8-membered heteromonocyclic groupcontaining 1 to 4 nitrogen atom(s) and saturated 3 to 8-memberedheteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), and the most preferred one may be pyridyl, imidazolyland morpholino.

Suitable example of “aryl” moiety in the term of “arylcarbamoyl whichmay have one or more suitable substituent(s)” can be referred toaforementioned “aryl”, in which the preferred one may be phenyl.

Suitable example of “lower alkyl” in the suitable substituent(s) of theterm “arylcarbamoyl which may have one or more suitable substituent(s)”can be referred to aforementioned “lower alkyl”, in which the preferredone may be (C₁-C₄)alkyl, and the most preferred one may be methyl andbutyl.

Suitable example of “higher alkyl” in the suitable substituent(s) of theterm “arylcarbamoyl which may have one or more suitable substituent(s)”can be referred to aforementioned “higher alkyl”, in which the preferredone may be (C₇-C₁₀)alkyl, and the most preferred one may be octyl.

Suitable example of “halo(lower)alkyl” in the suitable substituent(s) ofthe term “arylcarbamoyl which may have one or more suitablesubstituent(s)” may include tri-halo(lower)alkyl such astrichloromethyl, trichloroethyl, trichloropropyl, trifluoromethyl,trifluoroethyl, trifluoropropyl, tribromomethyl, tribromoethyl, and thelike, in which the preferred one may be tri-halo(C₁-C₄)alkyl, and themost preferred one may be trifluoromethyl.

Suitable example of “mono or di-lower alkylamino” in the suitablesubstituent(s) of the term “arylcarbamoyl which may have one or moresuitable substituent(s)” may include methylamino, dimethylamino,ethylamino, diethylamino, propylamino, isopropylamino, butylamino,isobutylamino, sec-butylamino, tert-butylamino, pentylamino,isopentylamino, tert-pentylamino, 1-methylpentylamino, neopentylamino,hexylamino, isohexylamino, and the like, in which the preferred one maybe di(C₁-C₄)alkylamino, and the most preferred one may be dimethylamino.

Suitable example of “lower alkoxy” in the suitable substituent(s) of theterm “arylcarbamoyl which may have one or more suitable substituent(s)”can be referred to aforementioned “lower alkoxy”, in which the preferredone may be (C₁-C₄)alkoxy, and the most preferred one may be methoxy.

Suitable example of “halo(lower)alkoxy” in the suitable substituent(s)of the term “arylcarbamoyl which may have one or more suitablesubstituent(s)” may include fluoromethoxy, fluoroethoxy,trifluoromethoxy, chloromethoxy, chloroethoxy, trichloroethoxy,bromomethoxy, iodoethoxy, and the like, in which the preferred one maybe halo(C₁-C₄)alkoxy, and the most preferred one may be fluoromethoxy.

Suitable example of “heterocyclic” moiety in the term of“heterocyclicarbamoyl which may have one or more suitablesubstituent(s)” can be referred to aforementioned “heterocyclic” moiety,in which the preferred one may be saturated or unsaturated 3 to8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s),unsaturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s) and unsaturated 3 to 8-membered heteromonocyclic groupcontaining 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), and themost preferred one may be piperidyl, tetrazolyl, indolyl and thiazolyl.

Suitable example of “ar(lower)alkyl” in the suitable substituent(s) ofthe term “heterocycliccarbamoyl which may have one or more suitablesubstituent(s)” may include “mono- or di- or tri-phenyl(lower)alkyl”such as benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl,phenylhexyl, benzhydryl, trityl, and the like, in which the preferredone may be benzyl.

Suitable example of “lower alkyl” moiety in the term of“heterocyclic(lower)alkyl” in the suitable substituent(s) of the term“heterocycliccarbamoyl which may have one or more suitablesubstituent(s)” can be referred to aforementioned “lower alkyl”, inwhich the preferred one may be (C₁-C₄)alkyl, and the most preferred onemay be methyl.

Suitable example of “heterocyclic” moiety in the term of“heterocyclic(lower)alkyl” in the suitable substituent(s) of the term“heterocycliccarbamoyl which may have one or more suitablesubstituent(s)” can be referred to aforementioned “heterocyclic”, inwhich the preferred one may be saturated 3 to 8-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s), and the mostpreferred one may be piperidyl.

Suitable example of “heterocyclic group” in the term of“heterocyclic(lower)alkyl which may be substituted with heterocyclicgroup” in the suitable substituent(s) of the term “heterocycliccarbamoylwhich may have one or more suitable substituent(s)” can be referred toaforementioned “heterocyclic group”, in which the preferred one may beunsaturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s), and the most preferred one may be indolyl.

Suitable example of “heterocyclic” moiety in the term of“heterocycliccarbonyl which may have one or more suitablesubstituent(s)” can be referred to aforementioned “heterocyclic” moiety,in which the preferred one may be saturated 3 to 8-memberedheteromonocyclic group containing to 4 nitrogen atom(s) and unsaturatedcondensed heterocyclic group containing 1 to 4 nitrogen atom(s), and themost preferred one may be piperidyl, piperazinyl and dihydroindolyl.

Suitable example of “ar(lower)alkyl” in the suitable substituent(s) ofthe term “heterocycliccarbonyl which may have one or more suitablesubstituent(s)” may include “mono- or di- or tri-phenyl(lower)alkyl”such as benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl,phenylhexyl, benzhydryl, trityl, and the like, in which the preferredone may be benzhydryl.

Suitable example of “heterocyclic group” moiety in the term“heterocyclic group which may have one or more suitable substituent(s)”in the suitable substituent(s) of the term “heterocycliccarbonyl whichmay have one or more suitable substituent(s)” can be referred toaforementioned “heterocyclic group”, in which the preferred one may beunsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4nitrogen atom(s), and the most preferred one may be pyridazinyl.

Suitable example of “suitable substituent(s)” in the term of“heterocyclic group which may be substituted with one or more suitablesubstituent(s)” may include oxo and aryl, in which the preferred one maybe oxo and phenyl.

Suitable example of “cyclo(lower)alkylcarbamoyl” may includecyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl,cyclohexylcarbamoyl, and the like, in which the preferred one may becyclo(C₄-C₆)alkylcarbamoyl, and the most preferred one may becyclohexylcarbamoyl.

Suitable example of “lower alkyl” in R⁵ can be referred toaforementioned “lower alkyl”, in which the preferred one may be(C₁-C₄)alkyl, and the most preferred one may be methyl.

Suitable example of “acyl(lower)alkoxy” may includecarbamoyl(lower)alkoxy, lower alkylcarbamoyl(lower)alkoxy,cyclo(lower)alkylcarbamoyl(lower)alkoxy, arylcarbamoyl(lower)alkoxy,heterocyclicccarbamoyl(lower)alkoxy, N-lower alkyl-loweralkylcarbamoyl(lower)alkoxy, ar(lower)alkylcarbamoyl(lower)alkoxy, loweralkoxy(lower)alkylcarbamoyl(lower)alkoxy, loweralkylthio(lower)alkylcarbamoyl(lower)alkoxy,di(lower)alkylamino(lower)alkylcarbamoyl(lower)alkoxy,heterocycliccarbonyl(lower)alkoxy, guanidinocarbonyl(lower)alkoxy,hydroxy(lower)alkylcarbamoyl(lower)alkoxy,halo(lower)alkylcarbamoyl(lower)alkoxy, protectedcarboxy(lower)alkylcarbamoyl(lower)alkoxy having protected carboxy,heterocyclic(lower)alkylcarbamoyl(lower)alkoxy,heterocycliccarbamoyl(lower)alkoxy having aryl(lower)alkyl,arylcarbamoyl(lower)alkoxy having higher alkyl,arylcarbamoyl(lower)alkoxy having lower alkyl,arylcarbamoyl(lower)alkoxy having halo(lower)alkyl,arylcarbamoyl(lower)alkoxy having nitro, arylcarbamoyl(lower)alkoxyhaving halogen, arylcarbamoyl(lower)alkoxy havingdi(lower)alkylamino(lower)alkyl, heterocycliccarbonyl(lower)alkoxyhaving benzhydryl, lower alkylcarbamoyl(lower)alkoxy having benzhydryl,heterocycliccarbamoyl(lower)alkoxy having heterocyclic(lower)alkylsubstituted with heterocyclic group, heterocycliccarbonyl(lower)alkoxyhaving heterocyclic group substituted with oxo and aryl, N-loweralkyl-ar(lower)alkylcarbamoyl(lower)alkoxy,N-ar(lower)alkyl-ar(lower)alkylcarbamoyl(lower)alkoxy, N-loweralkyl-heterocyclic(lower)alkylcarbamoyl(lower)alkoxy,arylcarbamoly(lower)alkoxy having lower alkyl,arylcarbamoyl(lower)alkoxy having lower alkoxy,arylcarbamoyl(lower)alkoxy having halogen, arylcarbamoyl(lower)alkoxyhaving halo(lower)alkoxy, arylcarbamoyl(lower)alkoxy havingdi(lower)alkylamino, N-aryl-aryl(lower)alkylcarbamoyl(lower)alkoxy,N-lower alkyl-cyclo(lower)alkylcarbamoyl(lower)alkoxy,

in which the preferred one may be carbamoyl(C₁-C₄)-alkoxy,(C₁-C₆)alkylcarbamoyl(C₁-C₄)alkoxy,cyclo(C₄-C₆)-alkylcarbamoyl(C₁-C₄)alkoxy, phenylcarbamoyl(C₁-C₄)alkoxy,carbamoyl(C₁-C₄)alkoxy substituted with unsaturated 3 to 8-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s),carbamoyl(C₁-C₄)alkoxy substituted with unsaturated condensedheterocyclic group containing 1 to 4 nitrogen atom(s),N-(C₁-C₄)alkyl-(C₁-C₆)alkylcarbamoyl(C₁-C₄)alkoxy,phenyl(C₁-C₄)alkylcarbamoyl (C₁-C₄)alkoxy,(C₁-C₄)alkoxy(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkoxy,(C₁-C₄)alkylthio(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkoxy,di(C₁-C₄)alkylamino(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkoxy,carbonyl(lower)alkoxy substituted with saturated 3 to 8-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s),guanidinocarbamoyl(C₁-C₄)alkoxy,hydroxy(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkoxy,tri-halo(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkoxy, esterifiedcarboxy(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkoxy having esterified carboxy,(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkoxy substituted with saturated 3 to8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1to 3 nitrogen atom(s), (C₁-C₄)alkylcarbamoyl(C₁-C₄)alkoxy substitutedwith unsaturated 3 to 8-membered heteromonocyclic group containing 1 to4 nitrogen atom(s), carbamoyl(C₁-C₄)alkoxy substituted with saturated 3to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s)having aryl(lower)alkyl, phenylcarbamoyl(C₁-C₄)alkoxy having(C₇-C₁₄)alkyl, phenylcarbamoyl(C₁-C₄)alkoxy having (C₁-C₄)alkyl,phenylcarbamoyl(C₁-C₄)alkoxy having tri-halo(C₁-C₄)alkyl,phenylcarbamoyl(C₁-C₄)alkoxy having nitro, phenylcarbamoyl(C₁-C₄)alkoxyhaving halogen, phenylcarbamoyl(C₁-C₄)alkoxy havingdi(C₁-C₄)alkylamino-(C₁-C₄)alkyl, carbonyl(C₁-C₄)alkoxy substituted withsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4nitrogen atom(s) having benzhydryl, (C₁-C₄)alkyl-carbamoyl(C₁-C₄)alkoxyhaving benzhydryl, carbamoyl(C_(l)-C₄)-alkoxy substituted withunsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2sulfur atom(s) and 1 to 3 nitrogen atom(s) having (C₁-C₄)alkylsubstituted with saturated 3 to 8-membered heteromonocyclic groupcontaining 1 to 4 nitrogen atom(s) substituted with unsaturatedcondensed heterocyclic group containing 1 to 4 nitrogen atom(s),carbonyl(C₁-C₄)alkoxy having unsaturated 3 to 8-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s) substitutedwith oxo and phenyl,N-(C₁-C₄)alkyl-phenyl-(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkoxy,N-phenyl(C₁-C₄)alkyl-phenyl(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkoxy,N-(C₁-C₄)alkyl-(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkoxy having unsaturated 3to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s),N-(C₁-C₄)alkyl-(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkoxy having unsaturatedcondensed heterocyclic group containing 1 to 4 nitrogen atom(s),phenylcarbamoyl(C₁-C₄)alkoxy having (C₁-C₄)alkyl,phenylcarbamoyl(C₁-C₄)alkoxy having (C₁-C₄)alkoxy,phenylcarbamoyl(C₁-C₄)alkoxy having halogen, carbamoyl(C₁-C₄)alkoxyhaving unsaturated 3 to 8-membered heteromonocyclic group containing 1to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), carbonyl(C₁-C₄)alkoxysubstituted with unsaturated condensed heterocyclic group containing 1to 4 nitrogen atom(s), phenylcarbamoyl (C₁-C₄)alkoxy havingdi-halo(C₁-C₄)alkoxy, phenylcarbamoyl(C₁-C₄)alkoxy havingdi(C₁-C₄)alkylamino, N-phenyl-phenyl(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkoxy,N-(C₁-C₄)alkyl-cyclo(C₄-C₆)alkylcarbamoyl(C₁-C₄)alkoxy,

and the most preferred one may be carbamoylmethoxy,ethylcarbamoylmethoxy, sec-butylcarbamoylmethoxy,n-butylcarbamoylmethoxy, hexylcarbamoylmethoxy,cyclohexylcarbamoylmethoxy, phenylcarbamoylmethoxy,tetrazolylcarbamoylmethoxy, indolylcarbamoylmethoxy,N-methyl-methylcarbamoylmethoxy, N-methyl-butylcarbamoylmethoxy,benzylcarbamoylmethoxy, methoxyethylcarbamoylmethoxy,methylthioethylcarbamoylmethoxy, dimethylaminoethylcarbamoylmethoxy,piperidinocarbonylmethoxy, guanidinocarbonylmethoxy,hydroxybutylcarbamoylmethoxy, 1-methylbutylcarbamoylmethoxy,2-hydroxypropylcarbamoylmethoxy, ethoxypropylcarbamoylmethoxy,hydroxypropylcarbamoylmethoxy, diethylaminopropylcarbamoylmethoxy,tri-fluoroethylcarbamoylmethoxy,1-ethoxycarbonyl-ethoxycarbonylmethylcarbamoylmethoxy,morpholinoethylcarbamoylmethoxy, pyridylethylcarbamoylmethoxy,pyridylmethylcarbamoylmethoxy, imidazolylpropylcarbamoylmethoxy,phenylbutylcarbamoylmethoxy, carbamoylmethoxy having piperidylsubstituted with benzyl, octylphenylcarbamoylmethoxy,butylphenylcarbamoylmethoxy, tri-fluoromethylphenylcarbamoylmethoxy,nitrophenylcarbamoylmethoxy, fluorophenylcarbamoylmethoxy,dimethylaminomethylbenzylcarbamoylmethoxy, piperadinocarbonylmethoxysubstituted with benzhydryl, benzhydrylmethylcarbamoylmethoxy,carbamoylmethoxy having thiazolyl having piperidinomethyl substitutedwith indolyl, piperidinocarbonylmethoxy having piridazinyl substitutedwith phenyl and oxo, N-methyl-benzylcarbamoylmethoxy,N-benzyl-benzylcarbamoylmethoxy, N-methoxy-indolylethylcarbamoylmethoxy,N-methyl-pyridylethylcarbamoylmethoxy, tolylcarbamoylmethoxy,methoxyphenylcarbamoylmethoxy, chlorophenylcarbamoylmethoxy,thiazolylcarbamoylmethoxy, dihydroindolylcarbonylmethoxy,di-fluoromethoxyphenylcarbamoylmethoxy, N-ethyl-propylcarbamoylmethoxy,N-methyl-methylpropylcarbamoylmethoxy, N-ethyl-butylcarbamoylmethoxy,N-methyl-hexylcarbamoylmethoxy, fluorophenylcarbamoylmethoxy,dimethylaminophenylcarbamoylmethoxy, N-phenyl-benzylcarbamoylmethoxy,N-methyl-phenethylcarbamoylmethoxy andN-methyl-cyclohexylcarbamoylmethoxy.

Suitable example of “lower alkyl” in R⁵ can be referred to aformentioned“lower alkyl”, in which the preferred one may be (C₁-C₄)alkyl, and themost preferred one may be methyl.

Suitable example of “aryl” in R⁵ can be referred to aforementioned“aryl”, in which the preferred one may be phenyl.

Suitable example of “lower alkylene” moiety in the term of “loweralkylene which may have one or more suitable substituent(s)” may includestraight or branched one such as methylene, ethylene, trimethylene,1-methylethylene, tetramethylene, pentamethylene, hexamethylene,methylmethylene, 1-ethylethylene, 2-ethylpropylene, and the like, inwhich the preferred one may be (C₁-C₄)alkylene, and the most preferredone may be methylene, ethylene and 1-methylethylene.

Suitable example of “suitable substituent(s)” moiety in the term of“lower alkylene which may have one or more suitable substituent(s)” mayinclude aryl, in which the preferred one may be phenyl.

Suitable example of “lower alkenylene” may include straight or branchedone having 2 to 6 carbon atom(s) such as vinylene, propenylene,butenylene, 1 or 2 or 3-pentenylene, 1 or 2 or 3-hexenylene,methylvinylene, ethylvinylene, 1 or 2 or 3-methylpropenylene, 1 or 2 or3-ethylpropenylene, 1 or 2 or 3 or 4-methyl-l or 2-butenylene, and thelike, in which the preferred one may be (C₂-C₄)alkenylene, and the mostpreferred one may be vinylene.

The processes for preparing the object compound [I] are explained indetail in the following.

Process 1

The object compound [I] or a salt thereof can be prepared by reacting acompound [II] with a compound [III] or a salt thereof.

Suitable salt of the compound [III] may be the same as those exemplifiedfor the compound [I].

The reaction is preferably carried out in the presence of a base such asan alkali metal carbonate [e.g. sodium carbonate, potassium carbonate,etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate,calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodiumbicarbonate, potassium bicarbonate, etc.], tri(lower)alkylamine [e.g.trimethylamine, triethylamine, etc.], picoline or the like.

The reaction is usually carried out in a conventional solvent, such asan alcohol [e.g. methanol, ethanol, propanol, isopropanol, etc.],diethyl ether, tetrahydrofuran, dioxane, or any other organic solventwhich does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction can becarried out under cooling to heating.

Process 2

The object compound [Ib] or a salt thereof can be prepared by subjectinga compound [Ia] or a salt thereof to elimination reaction of the aminoprotective group.

Suitable salts of the compounds [Ia] may be the same as thoseexemplified for the compound [I].

This reaction is carried out in accordance with a conventional methodsuch as hydrolysis, reduction or the like.

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid.

Suitable base may include an inorganic base and an organic base such asan alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal[e.g. magnesium, calcium, etc.], the hydroxide or carbonate orbicarbonate thereof, hydrazine, trialkylamine [e.g. trimethylamine,triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, orthe like.

Suitable acid may include an organic acid [e.g. formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.],an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuricacid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, etc.] andan acid addition salt compound [e.g. pyridine hydrochloride, etc.].

The elimination using trihaloacetic acid [e.g. trichloroacetic acid,trifluoroacetic acid, etc.] or the like is preferably carried out in thepresence of cation trapping agents [e.g. anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, analcohol [e.g. methanol, ethanol, etc.], methylene chloride, chloroform,tetrachloromethane, tetrahydrofuran, a mixture thereof or any othersolvent which does not adversely influence the reaction. A liquid baseor acid can be also used as the solvent. The reaction temperature is notcritical and the reaction is usually carried out under cooling toheating.

The reduction method applicable for the elimination reaction may includechemical reduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of metal [e.g. tin, zinc, iron, etc.] or metallic compound[e.g. chromium chloride, chromium acetate, etc.] and an organic orinorganic acid [e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.].

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts [e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.], palladium catalysts [e.g. spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium, palladium onbarium sulfate, palladium on barium carbonate, etc.], nickel catalysts[e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobaltcatalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts[e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reducedcopper, Raney copper, Ullman copper, etc.] and the like.

In case that the amino protective group is benzyl, the reduction ispreferably carried out in the presence of a combination of palladiumcatalysts [e.g. palladium black, palladium on carbon, etc.] and formicacid or its salt [e.g. ammonium formate, etc.].

The reduction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, an alcohol[e.g. methanol, ethanol, propanol, etc.], chlorobenzene,N,N-dimethylformamide, or a mixture thereof. Additionally, in case thatthe above-mentioned acids to be used in chemical reduction are inliquid, they can also be used as a solvent. Further, a suitable solventto be used in catalytic reduction may be the above-mentioned solvent,and other conventional solvent such as diethyl ether, dioxane,tetrahydrofuran, etc. or a mixture thereof.

The reaction temperature of this reduction is not critical and thereaction is usually carried out under cooling to heating.

The object compound [I] or a salt thereof possesses gut selectivesympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic andanti-pollakiuria activities, and are useful for the treatment and/orprevention of gastrointestinal disorders caused by smooth musclecontractions in human beings or animals, and more particularly tomethods for the treatment and/or prevention of spasm or hyperanakinesiain case of irritable bowel syndrome, gastritis, gastric ulcer, duodenalulcer, enteritis, cholecystapathy, cholangitis, urinary calculus and thelike; for the treatment and/or prevention of ulcer such as gastriculcer, duodenal ulcer, peptic ulcer, ulcer causes by non steroidalanti-inflammatory drugs, or the like; for the treatment and/orprevention of dysuria such as pollakiuria, urinary incontinence or thelike in case of nervous pollakiuria, neurogenic bladder dysfunction,nocturia, unstable bladder, cystospasm, chronic cystitis, chronicprostatitis, overflow incontinence, passive incontinence, refluxincontinence, urge incontinence, urinary incontinence, or the like; andfor the treatment and/or prevention of pancreatitis, obesity, diabetes,glycosuria, hyperlipidemia, hypertension, atherosclerosis, glaucoma,melancholia, depression, and the like.

The following compound to be used as the β₃ adrenergic receptor agonistwhich is shown by formulas (IV), (V), (VI), (VII) and (VII) are alsouseful for the therapeutic treatment of dysuria, and the like.

or a salt thereof, wherein

A is a bond, —(CH₂)_(n)— or CH(B)—, where n is an integer of 1 to 3 and

B is —CN, —CON(R⁹)R^(9′)or —CO₂R⁷;

R¹ is lower alkyl, aryl or arylalkyl;

R² is hydrogen, hydroxy, alkoxy, —CH₂OH, cyano, —C(O)OR⁷, —CO₂H, —CONH₂,tetrazole, —CH₂NH₂ or halogen;

R³ is hydrogen, alkyl, heterocycle or

R⁴ is hydrogen, alkyl or B;

R⁵, R^(5′), R⁸, R^(8′) and R^(8″) are independently hydrogen, alkoxy,lower alkyl, halogen, —OH, —CN, —(CH₂)_(n)NR⁶COR⁷, CON(R⁶)R^(6′),—CON(R⁶)OR^(6″), —CO₂R⁶, —SR⁷, —SOR⁷, —SO₂R⁷, —N(R⁶)SO₂R¹, —N(R⁶)R^(6′),—NR⁶COR⁷, —OCH₂CON(R⁶)R^(6′), —OCH₂CO₂R⁷ or aryl; or

R⁵ and R^(5′) or R⁸ and R^(8′) may together with the carbon atoms towhich they are attached form an aryl or heterocycle;

R⁶ and R^(6′) are independently hydrogen or lower alkyl; and

R⁷ is lower alkyl;

R⁹ and R^(9′) are independently hydrogen, lower alkyl, alkyl,cycloalkyl, arylalkyl, aryl, heteroaryl; or

R⁹ and R^(9′) may together with the nitrogen atom to which they areattached form a heterocycle;

with the proviso that when

A is a bond or —(CH₂)_(n) and

R³ is hydrogen or unsubstituted alkyl,

 then

R⁴ is B or substituted alkyl:

or a salt thereof, wherein

n is 0 to 5;

m is 0 or 1;

r is 0 to 3;

A is pyridinyl;

R¹ is (1) hydroxy, (2) oxo, (3) halogen, (4) cyano, (5) NR⁸R⁸, (6) SR⁸,(7) trifluoromethyl, (8) C₁-C₁₀ alkyl, (9) OR⁸, (10) SO₂R⁹, (11) OCOR⁹,(12) NR⁸COR⁹, (13) COR⁹, (14) NR⁸SO₂R⁹, (15) NR⁸CO₂R⁸, or (16) C₁-C₁₀alkyl substituted by hydroxy, halogen, cyano, NR⁸R⁸, SR⁸,trifluoromethyl, OR⁸, C₃-C₈ cycloalkyl, phenyl, NR⁸COR⁹, COR⁹, SO₂R⁹,OCOR⁹, NR⁸SO₂R⁹ or NR⁸CO₂R⁸;

R² and R³ are independently (1) hydrogen, (2) C₁-C₁₀ alkyl or (3) C₁-C₁₀alkyl with 1 to 4 substituents selected from hydroxy, C₁-C₁₀ alkoxy, andhalogen;

X is (1)—CH₂—, (2) —CH₂—CH₂—, (3) —CH═CH— or (4) —CH₂O—;

R⁴ and R⁵ are independently (1) hydrogen, (2) C₁-C₁₀ alkyl, (3) halogen,(4) NHR⁸, (5) OR⁸, (6) SO₂R⁹ or (7) NHSO₂R⁹;

R⁶ is (1) hydrogen or (2) C₁-C₁₀ alkyl;

R⁷ is Z—(R^(1a))_(n);

R^(1a) is (1) R¹, (2) C₃-C₈ cycloalkyl, (3) phenyl optionallysubstituted with up to 4 groups independently selected from R⁸, NR⁸R⁸,OR⁸, SR⁸ and halogen, or (4) 5 or 6-membered heterocycle with from 1 to4 heteroatoms selected from oxygen, sulfur and nitrogen, optionallysubstituted with up to four groups independently selected from oxo, R⁸,NR⁸R⁸, OR⁸, SR⁸, and halogen;

Z is (1) phenyl, (2) naphthyl, (3) a 5 or 6-membered heterocyclic ringwith from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,(4) a benzene ring fused to a C₃-C₈ cycloalkyl ring, (5) a benzene ringfused to a 5 or 6-membered heterocyclic ring with from 1 to 4heteroatoms selected from oxygen, sulfur and nitrogen, (6) a 5 or6-membered heterocyclic ring with from 1 to 4 heteroatoms selected fromoxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ringwith from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,or (7) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatomsselected from oxygen, sulfur and nitrogen fused to a C₃-C₈ cycloalkylring;

R⁸ is (1) hydrogen, (2) C₁-C₁₀ alkyl, (3) C₃-C₈ cycloalkyl, (4) Zoptionally having 1 to 4 substituents selected from halogen, nitro, oxo,NR¹⁰R¹⁰, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylthio, and C₁-C₁₀ alkylhaving 1 to 4 substituents selected from hydroxy, halogen, CO₂H,CO₂-C₁-C₁₀ alkyl, SO₂—C₁-C₁₀ alkyl, C₃-C₈ cycloalkyl, C₁-C₁₀ alkoxy, andZ optionally substituted by from 1 to 3 of halogen, C₁-C₁₀ alkyl orC₁-C₁₀ alkoxy, or (5) C₁-C₁₀ alkyl having 1 to 4 substituents selectedfrom hydroxy, halogen, CO₂H, CO₂—C₁-C₁₀ alkyl, SO₂—C₁-C₁₀ alkyl, C₃-C₈cycloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkyl, and Z optionally substituted byfrom 1 to 4 of halogen, C₁-C₁₀ alkyl or C₁-C₁₀ alkoxy;

R⁹ is (1) R⁸ or (2) NR⁸R⁸; and

R¹⁰ is (1) C₁-C₁₀ alkyl, or (2) two R¹⁰ groups together with the N towhich they are attached formed a 5 or 6-membered ring optionallysubstituted with C₁-C₁₀ alkyl:

or a salt thereof, wherein

X is hydrogen, halogen, trifluoromethyl or lower alkyl, and

R is hydrogen; lower alkyl which may have a suitable substituentselected from the group consisting of cyclo(C₃-C₇)alkyl, hydroxy, loweralkoxy, carboxy and lower alkoxycarbonyl; cyclo(c₃-C₇) alkyl or loweralkanoyl:

or a salt, ester or amide thereof, wherein

R¹ is a hydrogen, fluorine, chlorine or bromine atom or a hydroxyl,hydroxymethyl, methyl, methoxyl, amino, formamido, acetamido,methylsulphonylamido, nitro, benzyloxy, methylsulphonylmethyl, ureido,trifluoromethyl or p-methoxybenzylamino group;

R² is a hydrogen, fluorine, chlorine or bromine atom or a hydroxylgroup;

R³ is a hydrogen, chlorine or bromine atom or a hydroxyl group,

R⁴ is a hydrogen atom or a methyl group;

R⁵ is a hydrogen atom or a methyl group;

R⁶ is a hydrogen, fluorine or chlorine atom or a methyl, methoxyl orhydroxy group;

X is an oxygen atom or a bond;

Y is an alkylene group of up to 6 carbon atoms or a bond; and

Z is an alkylene, alkenylene or alkynylene group of up to 10 carbonatoms: or

or a salt thereof, wherein

R is hydrogen or methyl,

R is hydrogen, halogen, hydroxy, benzyloxy, amino or hydroxymethyl,

R² is hydrogen, hydroxymethyl, —NHR³, —SO₂NR⁴R ^(4′) or nitro,

R³ is hydrogen, methyl, —SO₂R⁵, formyl or —CONHR^(6′),

R⁴ and R^(4′) are independently hydrogen, lower alkyl or benzyl,

R⁵ is lower alkyl, benzyl or —NR⁴R^(4′),

R⁶ is hydrogen or lower alkyl,

R⁶′ is hydrogen or lower alkyl, and,

X is N, O, S or methylene;

when X is N, O or S,

then R⁹ is hydrogen,

either R⁷ or R⁸ is hydrogen, and

the other is hydrogen, amino, acetylamino or hydroxy;

when X is methylene,

then both R⁷ and R⁸ is hydrogen, and

R⁹ is hydrogen, amino, acetylamino or hydroxy.

The compounds (IV), (V), (VI), (VII) and (VIII) identified above or asalt thereof to be used in the present invention are the known ones anddisclosed in EP-A2-659737, U.S. Pat. No. 5,561,142, EP-A1-211721,EP-A1-023385, and WO97/25311, respectively.

In the formula (IV), the terms “alk” or “alkyl” refers to both straightand branched chain groups having 1 to 12 carbon atoms, preferably 1 to 8carbons. It is understood, therefore, that the terms “alk” and “alkyl”denote both unsubstituted groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, n-hexyl and the likeas well as substituted groups. The term “substituted alkyl” specificallydenotes an alkyl group as defined above having one or more of thefollowing substituents: halo (especially to form trihaloalkyl,particularly trichloromethyl or trifluoromethyl); aryl; cycloalkyl;hydroxy; amino; thiol; or Y, where Y is —CN, alkoxy, —CON(R⁶)R^(6′),—CO₂R⁶ or —N(R⁶)SO₂R¹.

The term “lower alkyl” as employed herein includes such alkyl groups asdescribed above containing 1 to 6 carbon atoms.

The term “alkoxy” refers to any of the above alkyl groups linked to anoxygen atom.

The term “lower alkoxy” refers to any of the above lower alkyl groupslinked to an oxygen atom.

The term “aryl” refers to monocyclic or bicyclic aromatic groupscontaining from 6 to 10 carbons in the ring portion, such as phenyl,naphthyl, or such groups optionally substituted with one or moresubstituents selected from hydrogen, alkoxy, lower alkyl, halogen, —OH,—CN, —(CH₂)_(n)NR⁶COR⁷, —CON(R⁶)R^(6′), —CON(R⁶)OR^(6′), —CO₂R⁶, —SOR⁷,—SO₂R⁷, —N(R⁶)SO₂R¹, —N(R⁶)R^(6′), —NR⁶COR⁷, —OCH₂CON(R⁶)R^(6′),—OCH₂CO₂R⁷ or aryl. Phenyl and substituted phenyl are preferred.

The term “halogen” or “halo” refers to chlorine, bromine, fluorine oriodine.

The term “heterocycle” refers to fully saturated or unsaturated rings of5 or 6 atoms containing one or two oxygen and/or sulfur atoms and/or oneto four nitrogen atoms provided that the total number of heteroatoms inthe ring is four or less. Preferred monocyclic heterocycle groupsinclude 2- and 3-thienyl, 2- and 3-furyl, 2-, 3- and 4-pyridyl andimidazolyl. The term heterocycle also includes bicyclic rings whereinthe five- or six-membered ring containing oxygen and/or sulfur and/ornitrogen atoms as defined above is fused to a benzene ring and thebicyclic ring is attached by way of an available carbon atom. Preferredbicyclic heterocycle groups include 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6-or 7-isoindolyl, 5-, 6-, 7- or 8-quinolinyl, 5-, 6-, 7- or8-isoquinolinyl, 4-, 5-, 6- or 7-benzothiazolyl, 4-, 5-, 6- or7-benzoxazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or7-benzoxadiazolyl, 4-, 5-, 6- or 7-benzofuranzanyl, 4-, 5-, 6- or7-benzodioxolyl and 4-, 5-, 6- or 7-benzofuran. The term “heterocycle”also includes such monocyclic and bicyclic rings wherein an availablecarbon atom is substituted with one or more substituents selected fromnitro, keto, azo, thiazo, hydrogen, alkoxy, lower alkyl, halogen, —OH,—CN, —(CH₂)_(n)NR⁶COR⁷, —CON(R⁶) R^(6′), —CON(R⁶)OR^(6′), —CO₂R⁶, —SR⁷,—SOR⁷, —SO₂R⁷, —N(R⁶)SO₂R¹, —N(R⁶)R^(6′), —NR⁶COR⁷, —OCH₂CON(R⁶)R^(6′),—OCH₂CO₂R⁷ or aryl.

In the formula (V), the alkyl groups specified above are intended toinclude those alkyl groups of the designated length in either a straightor branched configuration. Exemplary of such alkyl groups are methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl,isopentyl, hexyl, isohexyl, and the like.

The alkoxy groups specified above are intended to include those alkoxygroups of the designated length in either a straight or branchedconfiguration. Exemplary of such alkoxy groups are methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy,isopentoxy, hexoxy, isohexoxy and the like.

The term “halogen” is intended to include the halogen atoms fluorine,chlorine, bromine and iodine.

Examples of 5 and 6-membered heterocycles and fused heterocycles of A, Zand R^(1a) include pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl,imidazolyl, thiazolyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl,indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl,benzofuranyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl,tetrahydronaphthyl, dihydrobenzofuranyl, tetrahydroquinolinyl,furopyridine and thienopyridine.

The preferred values of A and Z are phenyl, naphthyl, benzene ring fusedto a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatomsselected from oxygen, sulfur and nitrogen, or heterocycles with from 1to 4 heteroatoms independently selected from one of oxygen or sulfur,and/or 1 to 4 nitrogen atoms.

The more preferred values of A are phenyl, pyridyl, quinolinyl,pyrimidinyl, pyrrolyl, thienyl, imidazolyl, and thiazolyl.

The more preferred values of Z are phenyl, naphthyl, quinolinyl,thienyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl,indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl,benzoxazinyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl,dihydrobenzofuranyl, triazolyl, tetrazolyl, oxadiazolyl, imidazolyl,oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, pyridyl,pyrimidyl, pyrazolyl, tetrahydrobenzothiazolyl and tetrahydroquinolinyl.When Z is attached to —NSO₂(CH₂)_(r)—, it is preferably phenyl, naphthylor a benzene ring fused to a 5 or 6-membered heterocyclic ring with from1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen. When Z ispart of the definition of R⁸, it is preferably phenyl, a 5 or 6-memberedheterocyclic ring with from 1 to 4 heteroatoms selected from oxygen,sulfur and nitrogen, a benzene ring fused to a 5 or 6-memberedheterocyclic ring with from 1 to 4 heteroatoms selected from oxygen,sulfur and nitrogen, or a 5 or 6-membered heterocyclic ring with from 1to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to aC₃-C₈ cycloalkyl ring.

The preferred heterocycles of R^(1a) are thienyl, thiadiazolyl,thiazolyl, tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl, thiazolyl,imidazolidinyl, isoxazolyl, pyridyl, pyrimidyl, and pyrazolyl.

Certain of the above defined terms may occur more than once in the aboveformula and upon such occurrence each term shall be definedindependently of the other; thus for example. NR⁸R⁸ may represent NH₂,NHCH₃, N(CH₃)CH₂CH₃, and the like.

In the formula (VI), the term “lower alkyl” may include straight orbranched one having 1 to 6 carbon atom(s), such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,3-pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, and thelike.

The term “halogen” may include fluorine, chlorine, bromine, iodine, andthe like.

The term “lower alkoxy” may include methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy,hexyloxy, and the like.

The term “lower alkoxycarbonyl” may include methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl,t-pentyloxycarbonyl, heptyloxycarbonyl, and the like.

The term “lower alkanoyl” may include acetyl, propanoyl, butanoyl,2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, and thelike.

The term “cyclo(C₃-C₇)alkyl” may include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and the like.

In the formula (VII), the term “alkylene” may include methylene,ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene,tert-butylene, pentylene, tert-pentylene, neo-pentylene, hexylene,iso-hexylene, heptylene, octylene, nonylene, decylene, and the like.

The term “alkenylene” may include vinylene, propenylene, butenylene, 1or 2 or 3-pentenylene, 1 or 2 or 3-hexenylene, methylvinylene,ethylvinylene, heptenylene, octenylene, nonenylene, decenylene, and thelike.

The term “alkynylene” may include ethynylene, propynylene, butynylene, 1or 2 or 3-pentynylene, 1 or 2 or 3-hexynylene, heptynylene, octynylene,nonynylene, decynylene, and the like.

In the formula (VIII), the term “lower alkyl” may include straight orbranched one having 1 to 6 carbon atom(s), such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,3-pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, and thelike.

In order to show the usefulness of the compounds (IV) to (VIII) for theprophylactic and therapeutic treatment of above-mentioned diseases in ahuman being or an animal, the pharmacological test data of therepresentative compounds thereof are shown in the following.

Test 1

Effect on the increase in intravesical pressure induced by carbachol inanesthetized dog

Test Compound

(1)N-[5-[2-[1-(3,4-Dimethoxyphenyl)-2-phenylethylamino]-1(R)-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide(This compound was obtained according to a similar manner to that ofExample 1 in EP-A2-659737.)

(2)N-[4-[2-[2(R)-Hydroxy-2-(pyridin-3-yl)ethylamino]ethyl]-phenyl]-4-[4-(3-cyclopentylpropyl)-5-tetrazolon-1-yl]-benzenesulfonamide(This compound was obtained according to a similar manner to that ofExample 70 in U.S. Pat. No. 5,561,142.)

(3)N-[5-[2-[2-(9H-Carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride (This compound was obtained according to a similar mannerto that of Example 2 in WO97/25311.)

Test Method

Female Beagle dogs weighing 8.0-15.0 kg were fasted for 24 hours andmaintained under halothane anesthesia. A 12F Foley catheter waslubricated with water soluble jelly, inserted into the urethral orificeand advanced approximately 10 cm until the balloon tip was placed wellinside the bladder. The balloon was then inflated with 5 ml of room airand catheter slowly withdrawn just part the first resistance that isfelt at the bladder neck. Urine was completely drained out throught thecatheter, and 30 ml of biological saline was infused. The catheter wasconnected to pressure transducer, and intravesical pressure wascontinuously recorded. The test compound was injected intravenously at 5minutes before the administration of carbachol (1.8 μg/kg)

Test Results Treatment Increase in intravesical pressure (mmHg) Control5.0 ± 0.9 Test Compound (1)  1.8 ± 0.3** (0.01 mg/kg) Control 5.0 ± 1.2Test Compound (2)  2.3 ± 1.5* (0.01 mg/kg) Control 5.0 ± 0.5 TestCompound (3)  1.7 ± 0.6** (0.01 mg/kg) *P < 0.05 vs Control (ANOVA) (N =4) **P < 0.01 vs Control (ANOVA) (N = 3)

The test compounds (1), (2) and (3) inhibited the increase inintravesical pressure induced by carbachol.

Test 2

Effect on cystometrogram in anesthetized rat

Test Compound

(4-1-2(S)-[(7-Ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino]-1(R)-(3-chlorophenyl)ethanolhydrochloride (This compound was obtained according to a similar mannerto that of Example 11 in EP-A1-211721.)

Test Method

Male S.D. rats, aged 7-9 weeks, were anesthetized with urethane (1.2g/kg, sc) and supine on a board. After a midline incision in theabdomen, the bladder was exposed. Polyethylene catheters, which wereused to measure the intravesical pressure and to infuse saline, wereinserted into the bladder through a small incision at the apex of thebladder dome. The bladder catheters were connected to an infusion pumpand pressure transducer respectively. Saline was infused a rate of 5.0ml/hr for 1 hour. Cystometrography was performed at 15 minutes intervalsfor 1 hour. The bladder capacity (volume) was calculated from the timerequired to fill the bladder. The test compound was administeredintravenously via femoral vein.

Test Result Vehicle compound (4) (0.01 mg/kg) Time (minutes) (relative %of before value)  (N = 5) Before (Control) 100 100  0-15 128 152 15-30111 146 30-45 114 143 45-60 104 151

The test compound (4) increased in bladder capacity at a dose of 0.01mg/kg.

Test 3

Effect on rhythmic contraction of bladder in anesthetized rat

Test Compound

(5) Methyl4-[2(R)-[2-(3-chlorophenyl)-2(R)-hydroxyethyl-amino]propyl]phenoxyacetate(This compound was obtained according to a similar manner to that ofExample 6 in EP-Al-023385.)

Test Method

Male S.D. rats, aged 7-8 weeks, were anesthetized with urethane (1.2g/kg, ip) and supine on a board. After a midline incision in theabdomen, the bladder was exposed. Balloon catheter, which was used tomeasure the intravesical pressure, was inserted into the bladder througha small incision at the apex of the bladder dome. The balloon was theninflated with distilled water and the balloon port of the catheter wasconnected to pressure transducer. Rhythmic contraction of bladderinduced by increase intravesical pressure to 10 mmHg. The test compoundwas administered intravenously via femoral vein.

Test Result compound (5) (0.1 mg/kg) Time (minutes) (relative % ofbefore value)  (N = 3) Before (Control) 100 30 66.3** **P < 0.01 vsBefore value (paired t-test)

The test compound (5) decreased in contractile force of bladder at adose of 0.1 mg/kg.

Suitable salt of the compounds in the present invention is apharmaceutically acceptable and conventional non-toxic salt, and mayinclude a salt with a base or an acid addition salt such as a salt withan inorganic base, for example, an alkali metal salt (e.g., sodium salt,potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt,magnesium salt, etc.), an ammonium salt; a salt with an organic base,for example, an organic amine salt (e.g., triethylamine salt, pyridinesalt, picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.); aninorganic acid addition salt (e.g., hydrochloride, hydrobromide,sulfate, phosphate, etc.); an organic carboxylic sulfonic acid additionsalt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate,fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); asalt with a basic or acidic amino acid (e.g., arginine, aspartic acid,glutamic acid, etc.).

The compounds in the present invention can be isolated and purified by aconventional method such as pulverization, recrystallization,column-chromatography, high-performance liquid chromatography (HPLC),reprecipitation, desalting resin column chromatography, or the like.

The compound in the present invention may be obtained as its hydrate,and its hydrate is included within the scope of present invention.

It is to be noted that each of the compounds in the present inventionmay include one or more stereoisomer such as optical isomer(s) andgeometrical isomer(s) due to asymmetric carbon atom(s) and doublebond(s) and all such isomers and the mixture thereof are included withinthe scope of the present invention.

The compounds in the present invention or a salt thereof includesolvated compound [e.g., enclosure compound (e.g., hydrate, etc.)].

The compounds in the present invention or a salt thereof include bothits crystal form and non-crystal form.

It should be understood that the compounds in the present invention mayinclude the prodrug form.

This application is based on applications No. PP2826/98 and PP5058/98filed in Australia, the content of which is incorporated hereinto byreference.

The compounds in the present invention may be obtained by methodsexemplified by EP-A2-659737, U.S. Pat. No. 5,561,142, EP-A1-211721,EP-A1-023385, or WO97/25311.

The patent, patent applications and publications cited herein areincorporated by reference.

The pharmaceutical composition of the present invention can be used inthe form of a pharmaceutical preparation, for example, in solid,semisolid or liquid form, which contains a compound in the presentapplication or a pharmaceutically acceptable salt thereof, as an activeingredient in admixture with an organic or inorganic carrier orexcipient suitable for rectal, pulmonary (nasal or buccal inhalation),nasal, ocular, external (copical), oral or parenteral (includingsubcutaneous, intravenous and intramuscular) administrations orinsufflation.

The active ingredient may be compounded, for example, with the usualnon-toxic, pharmaceutically acceptable carriers for tablets, pellets,troches, capsules, suppositories, creams, ointments, aerosols, powdersfor insufflation, solutions, emulsions, suspensions, and any other formsuitable for use. And, if necessary, in addition, auxiliary,stabilizing, thickening and coloring agents and perfumes may be used.

The compound or a salt thereof in the present invention is included inthe pharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of the diseases.

The pharmaceutical composition of the present invention can bemanufactured by the conventional method in this field of the art. Ifnecessary, the technique generally used in this field of the art forimproving the bioavailability of a drug can be applied to thepharmaceutical composition of the present invention.

For applying the composition to a human being or an animal, it ispreferable to apply it by intravenous (including i.v. infusion),intramuscular, pulmonary, or oral administration, or insufflation.

While the dosage of therapeutically effective amount of the compound inthe present invention varies from and also depends upon the age andcondition of each individual patient to be treated, in the case ofintravenous administration, a daily dose of 0.01-100 mg of the compoundin the present invention per kg weight of a human being or an animal, inthe case of intramuscular administration, a daily dose of 0.01-100 mg ofthe compound in the present invention per kg weight of a human being oran animal, in case of oral administration, a daily dose of 0.01-200 mgof the compound in the present invention per kg weight of a human beingor an animal is generally given for the prophylactic and/or therapeutictreatment of above-mentioned diseases in a human being or an animal.

The following Preparations and Examples are given for the purpose ofillustrating this invention.

Preparation 1

Under nitrogen, a solution ofN-benzyl-(3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(2.0 g) in tetrahydrofuran (20 ml) was added di-tert-butyl dicarbonate(1.4 g) at 5° C., and the solution was stirred at room temperature for2.5 hours. The resulting solution was evaporated in vacuo. The residuewas chromatographed (hexane-ethyl acetate) over silica gel to afford[8-(N-benzyl-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid ethyl ester (2.58 g).

NMR (CDCl₃, δ): 1.29 (3H, t, J=7.1 Hz), 1.08-1.63 (11H, m), 1.87-2.18(3H, m), 2.50-2.70 (3H, m), 3.17-3.35 (1H, m), 4.27 (2H, q, J=7.1 Hz),4.37-4.70 (2H, m), 4.55 (2H, s), 6.60 (1H, dd, J=2.5 and 8.1 Hz), 6.93(1H, d, J=8.3 Hz), 7.19-7.83 (4H, m)

Preparation 2

To a solution of[8-(N-benzyl-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid ethyl ester (2.5 g) in ethanol (25 ml) was added 1N sodiumhydroxide aqueous solution at 5° C., and the solution was stirred atroom temperature for 1 hour. The resulting solution was evaporated invacuo to afford sodium[8-(N-benzyl-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetate(2.35 g).

NMR (CDCl₃, δ): 1.04-1.60 (10H, m), 1.75-2.11 (3H, m), 2.41-2.67 (4H,m), 3.15-3.55 (1H, m) , 4.05 (2H, s), 4.27-4.65 (2H, m), 6.52 (2H, d,J=7.9 Hz), 6.88 (1H, d, J=8.2 Hz), 7.12-7.42 (5H, m)

Preparation 3

Under nitrogen, to a mixture of sodium[8-(N-benzyl-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetate(0.50 g) in dichloromethane (5 ml) were added 4N hydrogenchloride inethyl acetate (0.28 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.24 g), aniline (112 μl) and a catalytic amount of4-dimethylaminopyridine at 5° C., and the mixture was stirred at roomtemperature for 3 hours. The resulting mixture was poured into 1Nhydrogen chloride aqueous solution and extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium bicarbonatesolution and brine, dried over magnesium sulfate, and evaporated invacuo. The residue was chromatographed (hexane-ethyl acetate) oversilica gel to affordN-benzyl-N-tert-butoxycarbonyl-(3-N-phenylcarbamoylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(0.47 g)

NMR (CDCl₃, δ): 1.13-1.75 (11H, m), 1.90-2.25 (3H, m), 2.50-2.80 (3H,m), 3.24-3.38 (1H, m), 4.27-4.78 (2H, m), 4.53 (2H, s), 6.68 (1H, dd,J=2.5 and 8.1 Hz), 6.98 (1H, d, J=8.3 Hz), 7.12-7.43 (9H, m), 7.58-7.65(2H, m)

The following compound was obtained according to a similar manner tothat of Preparation 3.

Preparation 4

N-Benzyl-N-tert-butoxycarbonyl-(3-N-butylcarbamoylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine

NMR (CDCl₃, δ): 0.93 (3H, t, J=7.2 Hz), 1.10-2.20 (17H, m), 2.50-2.75(3H, m), 3.15-3.45 (4H, m), 4.28-4.77 (2H, m), 4.40 (2H, s), 6.60 (2H,dd, J=2.4 and 8.1 Hz), 6.95 (1H, d, J=8.3 Hz), 7.25-7.50 (5H, m)

Preparation 5

Under nitrogen, 4N hydrogenchloride in ethyl acetate (4 ml) was added toN-benzyl-N-tert-butoxycarbonyl-(3-N-phenylcarbamoylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(0.45 g) at room temperature, and the solution was stirred at the sametemperature for 3.5 hours. The resulting solution was evaporated invacuo. The residue was dissolved in a mixture of saturated aqueoussodium bicarbonate solution and ethyl acetate. After separation, theorganic layer was dried over magnesium sulfate and evaporated in vacuoto afford2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-N-phenylacetamide(346 mg).

NMR (CDCl₃, δ): 1.38-1.62 (1H, m), 1.63-2.14 (4H, m), 2.65-2.82 (3H, m),2.90-2.98 (2H, m), 3.82 (2H, ABq, J=3.7 and 12.7 Hz), 4.58 (2H, s), 6.71(1H, dd, J=2.7 and 8.2 Hz), 6.82 (1H, d, J=2.7 Hz), 7.04 (1H, d, J=8.2Hz), 7.13-7.42 (8H, m), 7.56-7.65 (2H, m)

MASS (m/z) 401 (M+H)⁺

The following compound was obtained according to a similar manner tothat of Preparation 5.

Preparation 6

2-(8-Benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-N-butylacetamide

NMR (CDCl₃, δ): 0.92 (3H, t, J=7.2 Hz), 1.25-1.61 (4H, m), 1.73-2.30(4H, m), 2.63-3.05 (5H, m), 3.34 (2H, q, J=6.9 Hz), 3.85 (2H, ABq,J=13.1 and 17.0 Hz), 4.45 (2H, s), 6.64 (1H, dd, J=2.7 and 8.2 Hz), 7.01(1H, d, J=8.2 Hz), 7.20-7.45 (5H, m)

MASS (m/z): 381 (M+H)⁺

Preparation 7

A solution ofN-benzyl-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amine(194 mg) and di-tert-butyl dicarbonate (174 mg) in tetrahydrofuran (2ml) was stirred at room temperature for 20 hours and partitioned betweenethyl acetate and an aqueous solution of sodium bicarbonate. The organiclayer was separated, washed with brine, dried over sodium sulfate, andevaporated in vacuo. The residue was chromatographed (toluene-ethylacetate) over silica gel (5.8 g) to affordN-benzyl-N-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamineas a pale yellow solid (196 mg).

mp: 150-156° C. (dec.)

IR (KBr): 3348 (br), 1666, 1246 cm⁻¹

NMR (DMSO-d₆, δ): 1.2-1.6 (10H, m), 1.96 (3H, m), 2.49-2.7 (3H, m),3.10-3.85 (2H, m), 4.30-4.7 (2H, m), 6.46-6.54 (2H, m), 6.77 (1H, m),7.15-7.36 (5H, m)

(+) API-ES MASS (m/z): 390 (M⁺+Na)

Preparation 8

A solution ofN-benzyl-N-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine(166 mg) and N-chlorosuccinimide (66.4 mg) in 1,4-dioxane (2 ml) wasrefluxed for 28 hours, cooled to room temperature, and partitionedbetween ethyl acetate and brine. The organic layer was separated, washedwith brine, dried over sodium sulfate, and evaporated in vacuo. Theresidue was chromatographed (toluene -ethyl acetate) over silica gel(3.6 g) to affordN-benzyl-N-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine(139 mg) as a colorless gum.

IR (KBr): 3411 (br) , 3263 (br) , 1655, 1252 cm⁻¹

Preparation 9

A mixture ofN-benzyl-N-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine(135 mg) and 4N hydrogen chloride in ethyl acetate (3 ml) was stirredunder ice-cooling for 2 hours and at room temperature for 5 hours andevaporated in vacuo. The residue was partitioned between ethyl acetateand an aqueous solution of sodium bicarbonate. The organic layer wasseparated, washed with brine, dried over sodium sulfate, and evaporatedin vacuo to affordN-benzyl-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amine(100 mg) as a yellow gum.

IR (KBr): 3419 (br), 1238 cm⁻¹

NMR (CDCl₃, δ): 1.48-1.59 (1H, m), 1.71-2.03 (3H, m), 2.3-3.16 (6H, m),3.78 (1H, d, J=13.0 Hz), 3.87 (1H, d, J=13.0 Hz), 6.73 (1H, s), 7.08(1H, s), 7.15-7.32 (6H, m)

Preparation 10

Under nitrogen, to a suspension of sodium hydride (60% in oil, 47 mg) inN,N-dimethylformamide (3 ml) was dropwise added8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (300 mg) inN,N-dimethylformamide (2 ml) at 5° C., and the mixture was stirred atthe same temperature for 30 minutes. To this one was added n-propylbromide (0.10 ml), and the mixture was stirred at the same temperaturefor 3 hours. The resulting mixture was poured into saturated aqueoussodium hydrogencarbonate, and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate, andevaporated in vacuo. The residue was purified by column chromatographyon silica gel (hexane:ethyl acetate =50:1 to 30:1) to giveN-benzyl-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(278 mg)

(+) ESI-MASS (m/z): 310 (M+H)⁺

The following compounds [Preparation 11 and 12] were obtained accordingto a similar manner to that of Preparation 10.

Preparation 11

N-Benzyl-(3-hexyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine

(+) APCI-MASS (m/z) 352 (M+H)⁺

Preparation 12

N-Benzyl-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine

NMR (CDCl₃, δ): 1.2-1.6 (2H, m), 1.7-2.1 (3H, m), 2.6-2.95 (5H, m),3.7-3.9 (2H, m), 5.03 (2H, s), 6.70 (1H, dd, J=2.7 and 8.2 Hz), 6.83(1H, d, J=2.6 Hz), 6.98 (1H, d, J=8.2 Hz), 7.2-7.5 (10H, m)

Preparation 13

Under nitrogen, a solution of(2S)-1-[N-benzyl-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol(20 g), chlorotriethylsilane (7.4 ml), imidazole (3.2 g) and4-dimethylaminopyridine (0.48 g) in N,N-dimethylformamide (200 ml) wasstirred at room temperature for 12 hours. The resulting mixture waspoured into water, and extracted with ethyl acetate-hexane (1:1). Theorganic layer was successively washed with saturated aqueous sodiumhydrogencarbonate and brine, dried over anhydrous magnesium sulfate, andevaporated in vacuo to giveN-benzyl-N-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-[(2S)-3-phenoxy-2-(triethylsilyloxy)-propyl]amine(25 g).

(+) ESI-MASS (m/z): 622 (M+H)⁺

Preparation 14

A mixture ofN-benzyl-N-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]amine(25 g) and 10% palladium on activated carbon (50% wet, 2.5 g) inmethanol (250 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 5 hours. After filtration, thefiltrate was evaporated in vacuo to give8-[(2S)-3-phenoxy-2-(triethylsilyloxy)propylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol(17 g).

(+) APCI-MASS (m/z): 442 (M+H)⁺

Preparation 15

Under nitrogen, a mixture of8-[(2S)-3-phenoxy-2-(triethylsilyloxy)propylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (17 g) and di-tert-butyldicarbonate (9.5 g) in tetrahydrofuran (180 ml) was stirred at roomtemperature for 18 hours. After evaporation, the residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate =20:1 to 10:1)to giveN-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine(17 g).

(+) APCI-MASS (m/z): 442 (M−Boc+2H)⁺

Preparation 16

Under nitrogen, to a suspension of sodium hydride (60% in oil, 12 mg) inN,N-dimethylformamide (2 ml) was dropwise addedN-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine(150 mg) in N,N-dimethylformamide (1 ml) at 5° C., and the mixture wasstirred at the same temperature for 30 minutes. To this one was addedethyl iodide (27 μl), and the mixture was stirred at room temperaturefor 2 hours. The resulting mixture was poured into saturated aqueoussodium hydrogencarbonate, and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate, andevaporated in vacuo. The residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=20:1) to giveN-(3-ethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine(130 mg).

NMR (CDCl₃, δ): 0.55-0.75 (6H, m), 0.9-1.0 (9H, m), 1.2-1.55 (4H, m),1.48 (9H, m), 1.9-2.2 (3H, m), 2.55-2.9 (3H, m), 3.1-3.65 (4H, m),3.85-4.1 (4H, m), 4.2-4.4 (1H, m), 6.55-6.7 (2H, m), 6.85-7.0 (4H, m),7.2-7.3 (2H, m)

(+) ESI-MASS (m/z): 592 (M+Na)⁺

The following compound was obtained according to a similar manner tothat of Preparation 16.

Preparation 17

N-(3-Allyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine

NMR (DMSO-d₆, δ): 0.55-0.75 (6H, m), 0.8-1.1 (9H, m), 1.2-1.6 (1H, m),1.48 (9H, m), 1.9-2.2 (3H, m), 2.6-2.9 (2H, m), 3.15-3.7 (4H, m),3.8-4.05 (2H, m), 4.25-4.5 (3H, m), 5.25-5.45 (2H, m), 5.95-6.15 (1H,m), 6.6-6.75 (2H, m), 6.8-7.0 (4H, m), 7.25-7.3 (2H, m)

Preparation 18

Under nitrogen, to dimethylsulfoxide (3 ml) was added potassiumhydroxide (31 mg) at room temperature, and the suspension was stirred atthe same temperature for 1 hour. To this one were addedN-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine(150 mg) and isopropyl bromide (78 μl), and the mixture was stirred atroom temperature for 3 hours. The resulting mixture was poured intoaqueous 10% sodium hydrogencarbonate, and extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous magnesiumsulfate, and evaporated in vacuo. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate =20:1) to giveN-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine(96 mg).

(+) APCI-MASS (m/z): 326 (M−Boc+2H)⁺

The following compounds [Preparations 19 to 21] were obtained accordingto a similar manner to that of Preparation 18.

Preparation 19

N-(3-Benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine

(+) APCI-MASS (m/z): 532 (M−Boc+2H)⁺

Preparation 20

N-Benzyl-N-[3-(3-cyanopyridin-2-yloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine

(+) APCI-MASS (m/z): 370 (M−Boc+2H)⁺

Preparation 21

N-Benzyl-N-(2-chloro-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine

(+) APCI-MASS (m/z): 316, 318 (M−Boc+2H)⁺

Preparation 22

Under nitrogen, to a solution ofN-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine(150 mg) in tetrahydrofuran (5 ml) was added triphenylphosphine (290mg), cyclopentanol (60 μl) and diethyl azodicarboxylate (174 μl) at 5°C., and the mixture was stirred at the same temperature for 5.5 hours.The resulting mixture was poured into saturated aqueous sodiumhydrogencarbonate, and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate, andevaporated in vacuo. The residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=10:1) to giveN-(3-cyclopentyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine(108 mg).

(+) APCI-MASS (m/z): 510 (M−Boc+2H)⁺

The following compound was obtained according to a similar manner tothat of Preparation 22.

Preparation 23

N-(3-Phenethyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl-tert-butoxycarbonylamine

(+) APCI-MASS (m/z): 546 (M−Boc+2H)⁺

Preparation 24

Under nitrogen, to a suspension of potassium carbonate (76 mg) in amixture of acetonitrile (5 ml) and N,N-dimethylformamide (2 ml) wasaddedN-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine(150 mg) at room temperature. After being stirred at the sametemperature for 30 minutes, to this one was an excessive amount ofbromofluoromethane, and the mixture was stirred for 12 hours. Theresulting solution was poured into saturated aqueous sodiumhydrogencarbonate, and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate, andevaporated in vacuo. The residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=10:1) to giveN-(3-fluoromethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine(130 mg).

(+) APCI-MASS (m/z): 474 (M−Boc+2H)⁺

Preparation 25

Under nitrogen, to a solution ofN-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine(150 mg) in dichloromethane (5 ml) were added pyridine (64 ml),4-nitrophenyl chloroformate (116 mg) and a catalytic amount of4-dimethylaminopyridine at 5° C. After being stirred at the sametemperature for 2 hours, to this one was added about 6.8M ammonia inethanol (0.5 ml), and the mixture was stirred at room temperature for 12hours. The resulting mixture was pured into water, and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate, and evaporated in vacuo. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=3:1) to giveN-[(2S)-3-phenoxy-2-(triethyl-silyloxy)propyl]-N-[3-carbamoyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine(129 mg).

(+) APCI-MASS (m/z): 485 (M−Boc+2H)⁺

Preparation 26

Under nitrogen, a mixture of8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (7.7 g) anddi-tert-butyl dicarbonate (6.9 g) in tetrahydrofuran (80 ml) was stirredat room temperature for 12 hours. After evaporation, the residue waspurified by column chromatography on silica gel (hexane:ethylacetate=7:1) to giveN-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine(10 g).

NMR (CDCl₁, δ): 1.1-1.7 (10H, m), 1.85-2.1 (3H, m), 2.45-2.7 (3H, m),3.15-3.85 (2H, m), 4.3-4.7 (2H, m), 5.05-5.25 (1H, m), 6.3-6.6 (2H, m),6.86 (2H, d, J=8.1 Hz), 7.15-7.4 (6H, m)

Preparation 27

ToN-benzyl-N-[3-(3-cyanopyridin-2-yloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine(480 mg) was added 4N hydrogen chloride in ethyl acetate (5 ml) at roomtemperature, and the mixture was stirred at the same temperature for 1hour. After evaporation in vacuo, the residue was dissolved into amixture of saturated aqueous sodium hydrogencarbonate and ethyl acetate,followed by being made basic with saturated aqueous sodiumhydrogencarbonate. After separation, the organic layer was washed withbrine, dried over anhydrous magnesium sulfate and evaporated in vacuo togive2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)oxy-3-cyanopyridine(339 mg).

(+) APCI-MASS (m/z): 370 (M+H)⁺

The following compounds [Preparations 28 to 30] were obtained accordingto a similar manner to that of Preparation 27.

Preparation 28

N-Benzyl-[3-(2-methoxyethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]amine

(+) APCI-MASS (m/z): 326 (M+H)⁺

Preparation 29

N-Benzyl-(3-phenyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine

(+) APCI-MASS (m/z): 328 (M+H)⁺

Preparation 30

N-Benzyl-(2-chloro-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine

(+) APCI-MASS (m/z): 316, 318 (M+H)⁺

Preparation 31

Under nitrogen, to dimethylsulfoxide (5 ml) was added potassiumhydroxide (34 mg) at room temperature, and the suspension was stirred atthe same temperature for 40 minutes. To this one were addedN-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine(200 mg) and 2-chloroethyl methyl ether (55 μl), and the mixture wasstirred at room temperature for 4 hours. The resulting mixture waspoured into saturated aqueous sodium hydrogencarbonate and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate, and evaporated in vacuo. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=10:1 to 5:1) to giveN-benzyl-N-[3-(2-methoxyethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine(213 mg).

(+) APCI-MASS (m/z): 326 (M−Boc+2H)⁺

Preparation 32

A solution of2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)aceticacid ethyl ester (320 mg) and 28% ammonium hydroxide (1 ml) in methanol(3 ml) was stirred at room temperature for 12 hours. The mixture wasevaporated in vacuo to give2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)acetamide(270 mg).

(+) APCI-MASS (m/z): 325 (M+H)⁺

Preparation 33

Under nitrogen, to a suspension of sodium hydride (60% in oil, 300 mg)in N,N-dimethylformamide (20 ml) was addedN-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine(2.5 g) in N,N-dimethylformamide (25 ml) at 5° C. After being stirred atroom temperature for 30 minutes, to this one were added ethylbromoacetate (0.75 ml) and tetra-n-butylammonium bromide (1.1 g) at 5°C., and the mixture was stirred at room temperature for 32 hours. Theresulting mixture was poured into saturated aqueous sodiumhydrogencarbonate and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate, andevaporated in vacuo. The residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=5:1) to give2-[8-(N-benzyl-N-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid ethyl ester (1.6 g).

NMR (CDCl₃, δ): 1.1-1.7 (10H, m), 1.30 (3H, t, J=7.1 Hz), 1.85-2.2 (3H,m), 2.5-2.7 (3H, m), 3.2-3.4 (1H, m), 4.27 (2H, q, J=7.2Hz), 4.3-4.7(2H, m), 4.54 (2H, s), 6.4-6.65 (2H, m), 6.93 (1H, d, J=8.3 Hz), 7.2-7.4(5H, m)

(+) APCI-MASS (m/z): 354 (M−Boc+2H)⁺

Preparation 34

To a solution of2-[8-(N-benzyl-N-tert-butoxycarbonyl-amino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid ethyl ester (1.6 g) in ethanol (16 ml) was added aqueous iN sodiumhydroxide at 5° C., and the mixture was stirred at room temperature for1 hour. After evaporation in vacuo, the residue was dissolved into amixture of aqueous 0.1N hydrochloric acid and ethyl acetate. Afterseparation, the organic layer was washed with brine, dried overanhydrous magnesium sulfate and evaporated in vacuo. The residue wastriturated with hexane and dried in vacuo to give2-[8-(N-benzyl-N-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid (1.3 g).

NMR (DMSO-d₆, δ): 1.1-1.7 (10H, m), 1.75-2.2 (3H, m), 2.45-2.7 (1H, m),3.15-3.75 (4H, m), 4.3-4.7 (2H, m), 4.57 (2H, s), 6.4-6.7 (2H, m), 6.96(1H, d, J=8.2 Hz), 7.2-7.5 (5H, m), 12.9 (1H, br s)

(+) APCI-MASS (m/z) 326 (M−Boc+2H)⁺

Preparation 35

Under nitrogen, a solution of2-[8-(N-benzyl-N-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid (300 mg) in dichloromethane (3 ml) were added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (150 mg),dimethylamine hydrochloride (63 mg) and 4-dimethylaminopyridine (130 mg)at 5° C., and the mixture was stirred at room temperature for 12 hours.The resulting mixture was poured into 0.1N hydrochloric acid andextracted with ethyl acetate. The organic layer was successively washedwith saturated aqueous sodium hydrogencarbonate and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=1:1) to giveN-benzyl-N-(3-N,N-dimethylcarbamoylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine(312 mg).

NMR (CDCl₃, δ) 1.1-1.65 (10H, m), 1.85-2.15 (3H, m), 2.5-2.7 (4H, m),2.98 (3H, s), 3.08 (3H, s), 3.2-3.45 (1H, m), 4.5-4.7 (2H, m), 4.60 (2H,s), 6.45-6.7 (2H, s), 6.93 (1H, d, J=8.2 Hz), 7.2-7.4 (5H, m)

(+) APCI-MASS (m/z) 353 (M−Boc+2H)⁺

Preparation 36

ToN-benzyl-N-(3-N,N-dimethylcarbamoylmethoxy-6,7,8,9-tetrahdyro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine(279 mg) was added 4N hydrogen chloride in ethyl acetate (3 ml), and themixture was stirred at room temperature for 1.5 hours. After evaporationin vacuo, the residue was dissolved into saturated aqueous sodiumhydrogencarbonate and ethyl acetate, followed by separation. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate andevaporated in vacuo. A mixture of the residue and 10% palladium onactivated carbon (50% wet, 100 mg) in methanol (5 ml) was stirred atroom temperature in the presence of hydrogen at an atmospheric pressurefor 7 hours. After filtration, the filtrate was evaporated in vacuo togive2-(8-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-N,N-dimethylacetamide(137 mg).

NMR (CDCl₃, δ) 1.4-2.1 (4H, m), 2.65-3.15 (5H, m), 2.98 (3H, m), 3.09(3H, s), 4.65 (2H, s), 6.68 (1H, dd, J=2.7 and 8.1 Hz), 6.77 (1H, d,J=2.7 Hz), 6.98 (1H, d, J=8.2 Hz)

(+) APCI-MASS (m/z): 263 (M+H)⁺

Preparation 37

Under nitrogen, to a solution of3-nitro-5,7,8,9-tetrahydrobenzocyclohepten-6-one (300 mg) in1,2-dichloroethane (10 ml) were added benzylamine (0.24 ml), sodiumtriacetoxyborohydride (460 mg) and acetic acid (0.17 ml) at roomtemperature, and the mixture was stirred at the same temperature for 5hours. The resulting mixture was poured into aqueous 1N sodium hydroxideand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and evaporated in vacuo.The residue was purified by column chromatography on silica gel(hexane:ethyl acetate=2:1 to 1:5) to giveN-benzyl-(3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (342mg).

(+) APCI-MASS (m/z): 297 (M+H)⁺

The following compound was obtained according to a similar manner tothat of Preparation 37.

Preparation 38

N-Benzyl-(6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-amine

(+) APCI-MASS (m/z): 252 (M+H)⁺

Preparation 39

Under nitrogen, to the solution of 1-tetralone (16 g) in dichloromethane(80 ml) were added zinc(II) iodide (0.69 g) and trimethylsilyl cyanide(15 g) at room temperature, and the mixture was stirred at the sametemperature for 3 hours. The resulting mixture was poured into saturatedaqueous sodium hydrogencarbonate and extracted with ethyl acetate. Theorganic layer was successively washed with saturated aqueous sodiumhydrogencarbonate and brine, dried over anhydrous magnesium sulfate andevaporated in vacuo to give crude1-(trimethylsilyloxy)-1-cyano-1,2,3,4-tetrahydronaphthalene (27 g),which was successively used in the next reaction.

The following compounds [Preparations 40 and 41] were obtained accordingto a similar manner to that of Preparation 39.

Preparation 40

7-Methyl-1-trimethylsilyloxy-1-cyano-1,2,3,4-tetrahydronaphthalene

Preparation 41

7-Chloro-1-trimethylsilyloxy-1-cyano-1,2,3,4-tetrahydronaphthalene

Preparation 42

Under nitrogen, to the suspension of lithium aluminum hydride (8.4 g) intetrahydrofuran (120 ml) was dropwise added1-trimethylsilyloxy-1-cyano-1,2,3,4-tetrahydronaphthalene (27 g) intetrahydrofuran (120 ml) at 5° C., and the mixture was stirred at roomtemperature for 24 hours. To the mixture were added sodium fluoride (37g) and water (12 ml) at 5° C., and the mixture was vigorously stirred atroom temperature for 30 minutes. The precipitate was removed byfiltration. The filtrate was evaporated in vacuo to give1-aminomethyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene (19 g)

(+) APCI-MASS (m/z): 178 (M+H)⁺

The following compounds [Preparations 43 and 44] were obtained accordingto a similar manner to that of Preparation 42.

Preparation 43

1-Aminomethyl-7-chloro-1-hydroxy-1,2,3,4-tetrahydronaphthalene

NMR (CDCl₃, δ): 1.8-2.2 (4H, m), 2.6-2.95 (4H, m), 7.00 (1H, d, J=8.2Hz), 7.13 (1H, dd, J=2.3 and 8.2 Hz), 7.52 (1H, d, J=2.2 Hz)

Preparation 44

1-Aminomethyl-7-methyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene

NMR (CDCl₃, δ): 1.5-2.2 (7H, m), 2.31 (3H, s), 2.6-2.9 (4H, m), 6.9-7.05(2H, m), 7.32 (1H, s)

Preparation 45

To a solution of 1-aminomethyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene(19 g) in 10% acetic acid in water (380 ml) was dropwise added sodiumnitrite (11 g) in water (56 ml) at 5° C., and the mixture was stirred atthe same temperature for 2 hours. The resulting mixture was diluted withethyl acetate and separated. The organic layer was successively washedwith water, saturated aqueous sodium hydrogencarbonate and brine, driedover anhydrous magnesium sulfate and evaporated in vacuo. The residuewas purified. by column chromatography on silica gel (hexane-ethylacetate) to give 5,7,8,9-tetrahydrobenzocyclohepten-6-one (9.3 g).

(+) APCI-MASS (m/z): 161 (M+H)⁺

The following compounds [Preparations 46 and 47] were obtained accordingto a similar manner to that of Preparation 45.

Preparation 46

3-Chloro-5,7,8,9-tetrahydrobenzocyclohepten-6-one

NMR (CDCl₃, δ): 1.9-2.1 (2H, m), 2.57 (2H, t, J=7.0 Hz), 2.9-3.0 (2H,m), 3.68. (2H, s), 7.09 (1H, d, J=7.8 Hz), 7.16 (1H, s), 7.18 (1H, d,J=7.8 Hz)

Preparation 47

3-Methyl-5,7,8,9-tetrahydrobenzocyclohepten-6-one

NMR (CDCl₃, δ): 1.9-2.05 (2H, m), 2.30 (3H, s), 2.57 (2H, t, J=6.8 Hz),2.85-2.95 (2H, m), 3.69 (2H, s), 6.95-7.1 (3H, m)

Preparation 48

A stirred solution of (2S)-1-phenoxy-2,3-epoxypropane (1.0 g) andconcentrated ammonium hydroxide (10 ml) in ethanol (10 ml) was sealed upat room temperature for 12 hours. The mixture was evaporated in vacuoand dried to give (2S)-1-amino-3-phenoxy-2-propanol (1.1 g).

(+) APCI-MASS (m/z): 168 (M+H)⁺

Preparation 49

To a mixture ofN-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine(1.01 g), 2,6-lutidine (0.38 ml) and N,N-dimethylaminopyridine (0.067 g)in dichloromethane (20 ml) was added dropwise trifluoromethanesulfonicanhydride (0.51 ml) at −30° C. The mixture was warmed to roomtemperature over 3 hours and then washed with water, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with a mixture of hexane andethyl acetate (20:1) to affordN-benzyl-N-tert-butoxycarbonyl-(3-trifluoromethylsulfonyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(0.98 g).

NMR (DMSO-d₆, δ): 1.14-1.50 (11H, m), 1.80-2.15 (3H, m), 2.60-2.80 (3H,m), 3.30-3.60 (1H, m), 4.25-4.62 (2H, m), 6.98-7.50 (8H, m)

(+) ESI-MASS (m/z): 522 (M+Na)⁺

Preparation 50

To a suspension ofN-benzyl-N-tert-butoxycarbonyl-(3-trifluoromethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(500 mg) in toluene (6 ml) and water (2 ml) were added phenylboronicacid (122 mg), sodium carbonate (210 mg) andtetrakis(triphenylphosphine)palladium(0) (35 mg), and the mixture wasstirred at 80° C. for 3.5 hours. The resulting mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous magnesium sulfate and evaporated invacuo. The residue was purified by column chromatography on silica gel(hexane:ethyl acetate=30:1 to 20:1) to giveN-benzyl-N-(3-phenyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine(494 mg).

(+) ESI-MASS (m/z): 450 (M+Na)⁺

Preparation 51

Under nitrogen, a suspension ofN-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine(300 mg) and N-chlorosuccinamide (110 mg) in 1,4-dioxane (5 ml) wasstirred at 10020 C. for 9 hours. The resulting mixture was poured intosaturated aqueous sodium hydrogencarbonate and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel (toluene:ethyl acetate=50:1 to 10:1)to giveN-benzyl-N-(2-chloro-3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine(152 mg) .

(+) APCI-MASS (m/z): 302, 304 (M−Boc+2H)⁺

Preparation 52

Under nitrogen, to a solution of (2R)-1-tosyloxy-2,3-epoxypropane (3.0g) in tetrahydrofuran (30 ml) were added N,N-diisopropylethylamine (2.5ml) and thiophenol (1.3 ml) at 5° C., and the mixture was stirred atroom temperature for 12 hours. The resulting mixture was poured intowater and extracted with ethyl acetate. The organic layer wassuccessively washed with saturated aqueous sodium hydrogencarbonate andbrine, dried over anhydrous magnesium sulfate and evaporated in vacuo.The residue was purified by column chromatography on silica gel(hexane:ethyl acetate=5:1 to 3:1) to give(2S)-3-phenylthio-1-tosyloxy-2-propanol (3.9 g).

NMR (CDCl₃, δ): 2.44 (3H, m), 2.75-3.25 (3H, m), 3.85-4.3 (3H, m),7.15-7.4 (7H, m), 7.7-7.8 (2H, m)

Preparation 53

Under nitrogen, to a solution of (2S)-3-phenylthio-1-tosyloxy-2-propanol(3.9 g) in ethanol (40 ml) was added 20% sodium methoxide in ethanol(4.7 ml) at 5° C., and the mixture was stirred at the same temperaturefor 30 minutes. After being filtrated off to remove precipitates, thefiltrate was concentrated in vacuo. The residue was dissolved into amixture of aqueous 0.1N sodium hydroxide and diethyl ether. Afterseparation, the organic layer was successively washed with water andbrine, dried over anhydrous magnesium sulfate and evaporated in vacuo.The residue was purified by column chromatography on silica gel(hexane:ethyl acetate=20:1 to 10:1) to give(2S)-1-phenylthio-2,3-epoxypropane (1.5 g).

(+) APCI-MASS (m/z): 167 (M+H)⁺

Preparation 54

Under nitrogen, to a solution of allylphenylamine (3 ml) indichloromethane (30 ml) were added pyridine (2.1 ml) and benzylchloroformate (3.5 ml) at 5° C., and the mixture was stirred at the sametemperature for 3 hours. The resulting mixture was poured into aqueous1N hydrogen chloride and extracted with ethyl acetate. The organic layerwas successively washed with saturated aqueous sodium hydrogencarbonateand brine, dried over anhydrous magnesium sulfate and evaporated invacuo. The residue was purified by column chromatography on silica gel(hexane:ethyl acetate=20:1 to 10:1) to giveN-allyl-N-phenylbenzyloxycarbonylamine (5.5 g).

(+) APCI-MASS (m/z): 268 (M+H)⁺

Preparation 55

Under nitrogen, to a solution of N-allyl-N-phenyl-benzyloxycarbonylamine(5.5 g) in dichloromethane (50 ml) was added m-chloroperbenzoic acid(3.9 g) at 5° C., and the mixture was stirred at room temperature for 3days. The resulting mixture was poured into aqueous sodiumhydrogensulfite and extracted with ethyl acetate. The organic layer wassuccessively washed with saturated aqueous sodium hydrogencarbonate andbrine, dried over anhydrous magnesium sulfate and evaporated in vacuo.The residue was purified by column chromatography on silica gel(hexane:ethyl acetate=10:1 to 5:1) to give1-(N-benzyloxycarbonyl-N-phenylamino)-2,3-epoxypropane (2.2 g).

(+) APCI-MASS (m/z): 284 (M+H)⁺

Preparation 56

To a suspension of but-3-butenylbenzene (3 ml) and sodium hydrogencarbonate (2.5 g) in a mixture of dichloromethane (200 ml) and water (60ml) was added small portions of m-chloroperbenzoic acid (3.5 g) at roomtemperature, and the mixture was stirred at the same temperature for 4hours. After separation, the organic layer was successively washed withsaturated aqueous sodium hydrogencarbonate and brine, dried overanhydrous magnesium sulfate and evaporated in vacuo. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=100:3) to give 2-phenethyloxirane (970 mg).

NMR (CDCl₃, δ): 1.7-1.9 (2H, m), 2.45-2.5 (1H, m), 2.7-3.0 (4H, m),7.1-7.4 (5H, m)

Preparation 57

A mixture of N-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-5benzocyclohepten-6-yl)amine (1.0 g) and 10% palladium on activatedcarbon (50% wet, 300 mg) in methanol (10 ml) was stirred at roomtemperature in the presence of hydrogen at an atmospheric pressure for5.5 hours. After filtration, the filtrate was evaporated in vacuo togive 3-methoxy-(6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (720mg).

NMR (CDCl₃, δ): 1.4-1.6 (1H, m), 1.7-2.0 (2H, m), 2.1-2.3 (1H, m),2.7-2.75 (2H, m), 2.85-3.3 (3H, m), 3.76 (3H, s), 6.66 (1H, dd, J=2.7and 8.2 Hz), 6.76 (1H, d, J=2.6 Hz), 7.00 (1H, d, J=8.2 Hz)

The following compounds [Preparation 58 and 59] were obtained accordingto a similar manner to that of Preparation 57.

Preparation 58

2-(8-Amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)acetic acidtert-butyl ester

NMR (CDCl₃, δ) 1.3-2.1 (4H, m), 1.49 (9H, s), 2.65-3.1 (5H, m), 4.48(2H, m), 6.61 (1H, dd, J=2.7 and 8.2 Hz), 6.73 (1H, d, J=2.7 Hz), 6.98(1H, d, J=8.2 Hz)

Preparation 59

2-(8-Amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-N-phenylacetamide

NMR (CDCl₃, δ): 1.45-2.15 (4H, m), 2.7-3.1 (5H, m), 4.58 (2H, m), 6.72(1H, dd, J=2.7 and 8.2 Hz), 6.83 (1H, d, J=2.7 Hz), 7.04 (1H, d, J=8.2Hz), 7.1-7.25 (1H, m), 7.3-7.4 (2H, m), 7.55-7.7 (2H, m), 8.30 (1H, brs)

(+) ESI-MASS (m/z): 311 (M+H)⁺

Preparation 60

To a solution ofN-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine(500 mg) in ethyl acetate (5 ml) was added 4N hydrogen chloride in ethylacetate (5 ml) at room temperature, and the mixture was stirred at thesame temperature for 1 hour. The mixture was poured into a mixture ofsaturated aqueous sodium hydrogencarbonate and ethyl acetate, followedby being made basic with saturated aqueous sodium hydrogencarbonate.After separation, the organic layer was dried over anhydrous magnesiumsulfate and evaporated in vacuo to give crude8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol.

Under nitrogen, to a suspension of sodium hydride (60% in oil, 60 mg) inN,N-dimethylformamide (3 ml) was added above obtained one inN,N-dimethylformamide (4 ml) at 5° C. After being stirred at roomtemperature for 30 minutes, to this one were added tert-butylbromoacetate (0.22 ml) and tetra-n-butylammonium bromide (220 mg) at 5°C., and the mixture was stirred at room temperature for 6 hours. Theresulting mixture was poured into saturated aqueous sodiumhydrogencarbonate and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel (chloroform:methanol=50:1 to 20:1) to give2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy) aceticacid tert-butyl ester (474 mg)

(+) APCI-MASS (m/z): 382 (M+H)⁺

Preparation 61

A mixture of 6-(4-nitrophenylazo)pyridin-3-ol (300 mg) and 20% palladiumhydroxide on carbon (60 mg) in a mixture of acetic acid (30 ml) andmethanol (30 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 70 minutes. After filtration,the filtrate was evaporated in vacuo. Under nitrogen, to a mixture ofthe residue in dichloromethane (10 ml) was addedbis(trimethylsilyl)acetamido (6.0 ml) at 5° C. After being stirred atroom temperature for 30 minutes, to this one was added benzylchloroformate (0.54 ml) at 5° C., and the mixture was stirred at thesame temperature for 3 hours. The resulting mixture was poured intosaturated aqueous sodium hydrogencarbonate and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and evaporated in vacuo. To the residue was addedchloroform, and insoluble materials were filtered off. After thefiltrate was evaporated in vacuo, the residue was purified by columnchromatography on silica gel (chloroform:methanol=50:1 to 20:1),followed by crystallization from toluene-methanol to give2-benzyloxy-carbonylamino-5-hydroxypyridine (159 mg).

(+) APCI-MASS (m/z): 245 (M+H)⁺

Preparation 62

Under nitrogen, to a suspension of sodium hydride (60% in oil, 189 mg)in N,N-dimethylformamide (20 ml) was dropwise added2-benzyloxycarbonylamino-5-hydroxypyridine (1.1 g) inN,N-dimethylformamide (12 ml) at 5° C., and the mixture was stirred atroom temperature for 1 hour. To this one was added(2S)-(+)-1-tosyloxy-2,3-epoxypropane (1.1 g) at 5° C., and the mixturewas stirred at room temperature for 7 hours. The resulting mixture waspoured into saturated aqueous sodium hydrogencarbonate and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and evaporated in vacuo. The residue waspurified by column chromatography on silica gel (chloroform:ethylacetate=9:1) to give2-benzyloxycarbonylamino-5-[(2S)-oxiranylmethoxy]pyridine (780 mg).

(+) APCI-MASS (m/z): 301 (M+H)⁺

Preparation 63

To a mixture of 8-methoxy-1-tetralone (2.66 g) and zinc iodide (0.096 g)in dichloromethane (13 ml) was dropwise added trimethylsilylcyanide(2.65 ml) under a nitrogen atmosphere. The reaction mixture was stirredat room temperature overnight and then poured into a saturated aqueoussodium bicarbonate solution. The product was extracted with ethylacetate, and the extract was washed with a saturated aqueous sodiumbicarbonate solution and brine, dried over magnesium sulfate, andevaporated in vacuo. The residue was purified by column chromatographyon silica gel eluting with a mixture of hexane and ethyl acetate (4:1)to afford1-cyano-8-methoxy-1-trimethylsilyloxy-1,2,3,4-tetrahydronaphthalene(3.64 g).

NMR (DMSO-d₆, δ): 0.15 (9H, s), 1.70-1.81 (2H, m), 2.09-2.38 (2H, m),2.70-2.77 (2H, m), 3.84 (3H, s), 6.76 (1H, d, J=8.0 Hz), 6.92 (1H, d,J=8.0 Hz), 7.29 (1H, d, J=8.0, 8.0 Hz)

(+) ESI-MASS (m/z): 298 (M+Na)⁺

Preparation 64

To a mixture of lithiumaluminumhydride (0.99 g) in tetrahydrofuran (18ml) was added dropwise a solution of1-cyano-8-methoxy-1-trimethylsilyloxy-1,2,3,4-tetrahydronaphthalene(3.59 g) in tetrahydrofuran (18 ml) under ice-cooling and a nitrogenatmosphere. After stirring at room temperature for 3 hours, sodiumfluoride (1.09 g) and water (1.41 ml) were added to the reaction mixtureunder ice-cooling. After stirring for additional 30 minutes, insolublematerials were filtered off and washed with 5% ethanol in ethyl acetate.The filtrate was evaporated in vacuo to afford1-aminomethyl-1-hydroxy-8-methoxy-1,2,3,4-tetrahydronaphthalene (2.60g), which was used in the next step without purification.

NMR (DMSO-d₆, δ): 1.38-1.72 (3H, m), 2.07-2.14 (1H, m), 2.62-2.91 (6H,m), 3.77 (3H, s), 6.68 (1H, d, J=7.8 Hz), 6.80 (1H, d, J=7.8 Hz), 7.09(1H, dd, J=7.8, 7.8 Hz)

(+) ESI-MASS (m/z): 190 (M−OH)⁺

Preparation 65

To a suspension ofl-aminomethyl-1-hydroxy-8-methoxy-1,2,3,4-tetrahydronaphthalene (2.54 g)in 10% acetic acid was added dropwise a solution of sodium nitrite (1.27g) in water (6.4 ml) under ice-cooling. The mixture was stirred at thesame temperature for 2 hours and then partitioned between ethyl acetateand water. The organic layer was separated, washed with an aqueoussodium bicarbonate solution and brine, dried over magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel eluting with a mixture of hexane and ethyl acetate (10:1)to afford 4-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (1.08g).

NMR (DMSO-d₆, δ): 1.77-1.91 (2H, m), 2.47 (2H, t, J=7.0 Hz), 2.85-2.92(2H, m), 3.76 (3H, s), 3.76 (2H, s), 6.76 (1H, d, J=7.5 Hz), 6.88 (1H,d, J=7.5 Hz), 7.16 (1H, dd, J=7.5 and 7.5 Hz)

(+) ESI-MASS (m/z): 213 (M+Na)⁺

Preparation 66

A solution of 4-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one(500 mg) and benzylamine (0.29 ml) in the presence of catalytic amountsof p-toluenesulfonic acid monohydrate in toluene (5 ml) was refluxed for2 hours to remove water as the toluene azeotrope, and then the mixturewas evaporated in vacuo. To the solution of the residue in methanol (5ml) was added sodium borohydride (99 mg) under nitrogen at 5° C., andthe mixture was stirred at room temperature for 12 hours. After theresulting mixture was evaporated in vacuo, the residue was dissolvedinto ice-cold water and ethyl acetate. After separation, the organiclayer was washed successively with water and brine, dried over anhydrousmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=5:1 to 1:1) togiveN-benzyl-(4-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(660 mg).

NMR (DMSO-d₆, δ): 1.17-1.37 (1H, m), 1.53-2.02 (3H, m), 2.25-2.38 (1H,m), 2.50-3.80 (3H, m), 3.26-3.32 (2H, m), 3.67-3.86 (2H, m), 3.77 (3H,s), 6.68 (1H, d, J=7.5 Hz), 6.79 (1H, d, J=7.5 Hz), 7.01 (1H, dd, J=7.5and 7.5 Hz), 7.17-7.30 (5H, m)

(+) ESI-MASS (m/z): 282 (M+H)⁺

Preparation 67

Into a mixture ofN-benzyl-N-(3-trifluoromethyl-sulfonyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine(0.94 g), palladium acetate (0.084 g), 1,3-bis(diphenylphosphino)propane(0.16 g), triethylamine (0.79 ml) in methanol (2.8 ml) andN,N-dimethylformamide (7 ml) was introduced carbon oxide gas at roomtemperature for 1 hour. Then the mixture was heated at 75° C. for 2.5hours with carbon oxide gas bubbling. After cooling, the reactionmixture was partitioned between water and ethyl acetate. The organiclayer was separated, washed with water (twice) and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with a mixture of hexane andethyl acetate (10:1) to afford8-(N-benzyl-N-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-carboxylicacid methyl ester (0.76 g).

NMR (DMSO-d₆, δ) 1.13-1.50 (11H, m), 1.79-2.13 (3H, m), 2.58-2.79 (3H,m), 3.44-3.74 (1H, m), 3.83 (3H, s), 4.30-4.62 (2H, m), 7.20-7.38 (6H,m), 7.50-7.60 (1H, m), 7.67 (1H, d, J=7.7 Hz)

(+) ESI-MASS (m/z): 432 (M+Na)⁺

Preparation 68

To a solution of8-(N-benzyl-N-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylicacid methyl ester (10.07 g) in dichloromethane (100 ml) was addedtrifluoroacetic acid (9.47 ml), and the mixture was stirred at roomtemperature overnight. The mixture was evaporated in vacuo andpartitioned between ethyl acetate and an aqueous sodium bicarbonatesolution. The organic layer was separated, washed with water and brine,dried over magnesium sulfate and evaporated in vacuo. The residue waspurified by column chromatography on silica gel eluting with a mixtureof chloroform and methanol (20:1) to afford8-benzylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acidmethyl ester (7.78 g).

NMR (DMSO-d₆, δ) 1.24-1.43 (1H, m), 1.59-2.08 (4H, m), 2.42-2.50 (1H,m), 2.76-3.03 (4H, m), 3.75 (2H, d, J=3.1 Hz), 3.83 (3H, s), 7.16-7.36(6H, m), 7.67 (1H, dd, J=7.7, 1.8 Hz), 7.75 (1H, d, J=1.8 Hz)

(+) ESI-MASS (m/z) 310 (M+H)⁺

Preparation 69

To a mixture of8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxpropyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylicacid methyl ester (4.80 g), imidazole (1.68 g) and catalytic amount ofN,N-dimethylaminopyridine in N,N-dimethylformamide (100 ml) was addedtriethylsilyl chloride (3.82 ml) under ice-cooling. The reaction mixturewas stirred at room temperature for 6 hours and partitioned betweenethyl acetate and aqueous sodium bicarbonate solution. The organic layerwas separated, washed with water (twice) and brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel eluting with a mixture of hexane and ethylacetate (20:1) to afford8-(N-tert-butoxycarbonyl-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)-propyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylicacid methyl ester (6.07 g).

NMR (DMSO-d₆, δ): 0.50-0.67 (6H, m), 0.83-0.95 (9H, m), 1.13-1.37 (1H,m), 1.42 (9H, s), 1.89-2.22 (3H, m), 2.68-2.98 (3H, m), 3.20-3.48 (4H,m), 3.81, 3.83 (total 3H, s), 3.83-3.92 (1H, m), 3.97-4.07 (1H, m),4.20-4.37 (1H, m), 6.86-6.97 (3H, m), 7.18-7.34 (3H, m), 7.68-7.75 (2H,m)

(+) APCI-MASS (m/z): 484 (M−Boc+2H)⁺

Preparation 70

To a cold (−78° C.) solution of8-[N-tert-butoxycarbonyl-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylicacid methyl ester (5.90 g) in tetrahydrofuran (120 ml) was addeddropwise a solution of diisobutylaluminum hydride in hexane (0.95M, 53.2ml). The reaction mixture was warmed to room temperature over 4 hours,and then saturated sodium bicarbonate solution was added dropwise to themixture. The resulting precipitate was filtered off and washed withethyl acetate. The filtrate was extracted with ethyl acetate, and theorganic layer was washed with water and brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel eluting with a mixture of hexane and ethylacetate (5:1) to affordN-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxy-carbonylamine(5.20 g).

NMR (DMSO-d₆, δ): 0.52-0.68 (6H, m), 0.85-0.97 (9H, m), 1.08-1.38 (1H,m), 1.41 (9H, s), 1.80-2.20 (3H, m), 2.50-2.88 (3H, m), 3.15-3.52 (4H,m), 3.80-3.90 (1H, m), 3.94-4.05 (1H, m), 4.22-4.40 (1H, m), 4.41 (2H,d, J=4.5 Hz), 5.06 (1H, t, J=4.5 Hz), 6.83-7.03 (6H, m), 7.30 (2H, dd,J=7.4 and 7.4 Hz)

(+) APCI-MASS (m/z): 456 (M−Boc+2H)⁺

Preparation 71

To a mixture ofN-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyl-oxy)propyl]-tert-butoxycarbonylamine(1.93 g) and triethylamine (0.58 ml) in dichloromethane (40 ml) wasadded dropwise methanesulfonyl chloride (0.27 ml) under ice-cooling.After stirring at room temperature for 6 hours, the reaction mixture waswashed successively with water, sodium bicarbonate solution, water andbrine. The organic layer was dried over magnesium sulfate and evaporatedin vacuo to afford crudeN-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-N-(3-methylsulfonyloxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine(2.18 g) which was used without purification.

Preparation 72

To a solution ofN-tert-butoxycarbonyl-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-(3-N,N-dimethylamino-methyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (0.60 g) in tetrahydrofuran (3 ml) was added a solution ofdimethylamine in tetrahydrofuran (2M, 1.89 ml) under ice-cooling. Themixture was stirred at room temperature overnight and then partitionedbetween water and ethyl acetate. The organic layer was separated, washedwith water and brine, dried over magnesium sulfate and evaporated invacuo. The residue was purified by column chromatography on silica geleluting with a mixture of chloroform and methanol (50:1 to 20:1) toaffordN-(3-N,N-dimethylaminomethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbononylamine(0.41 g).

NMR (DMSO-d₆, δ): 0.43-0.67 (6H, m), 0.82-0.98 (9H, m), 1.10-1.35 (1H,m), 1.41 (9H, s), 1.81-2.08 (3H, m), 2.11 (6H, s), 2.50-2.90 (3H, m),3.17-3.58 (5H, m), 3.78-4.22 (4H, m), 6.87-7.04 (6H, m), 7.22-7.34 (2H,m) (0.41 g).

(+) APCI-MASS (m/z): 583 (M+H)⁺

Preparation 73

A mixture of8-benzylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acidmethyl ester (4.21 g) and sodium methoxide (2.21 g) in formamide (42 ml)was heated at 110° C. for 2 hours. After cooling, the reaction mixturewas poured into water, and the product was extracted with ethyl acetate.The organic layer was washed with water (twice) and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with a mixture of chloroformand methanol (30:1 to 10:1) to afford8-benzylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxamide(2.71 g).

NMR (DMSO-d₆, δ): 1.24-1.42 (1H, m), 1.59-2.05 (4H, m), 2.40-2.50 (1H,m), 2.70-3.01 (4H, m), 3.67-3.84 (2H, m), 7.13 (1H, d, J=7.7 Hz),7.18-7.36 (6H, m), 7.59 (1H, dd, J=7.7 and 1.8 Hz), 7.70 (1H, d, J=1.8Hz), 7.86 (1H, s)

(+) APCI-MASS (m/z): 295 (M+H)⁺

Preparation 74

To a solution of(R)-4-(3-toluenesulfonyloxy-2-hydroxy)propyl-1-benzyloxybenzene (110 mg)in acetonitrile (10 ml), a solution of nitronium tetrafluoroborate (536mg) in acetonitrile (10 ml) was added dropwise with ice-bath cooling.The reaction mixture was stirred for 0.5 hour and worked up in a usualmanner. The crude product was purified by a column chromatography (SiO₂50 cm³, eluent; 33% ethyl acetate-hexane) to give(R)-1-(3-toluenesulfonyloxy-2-hydroxy)propyl-3-nitro-4-benzyloxybenzene(259 mg) as an oil.

IR (Film) 1623, 1533, 1356, 1267, 1174, 1095, 984, 816 cm⁻¹

NMR (CDCl₃, δ): 2.17 (1H, d, J=4.4 Hz), 2.46 (3H, s), 2.7-2.8 (2H, m),3.9-4.2 (3H, m), 5.21 (2H, s), 7.06 (1H, t, J=8.7 Hz), 7.3-7.5 (7H, m),7.66 (1H, d, J=2.1 Hz), 7.7-7.9 (3H, m)

Preparation 75

To a solution of 4-benzyloxybromobenzene (263 mg) in dry tetrahydrofuran(3 ml), butyllithium (1.54M hexane solution, 0.71 ml) was added dropwiseat −78° C. under nitrogen, and the resulting mixture was stirred for 30minutes. To the reaction mixture, boranetrifluoride diethyl ether (123μl), and a solution of (R)-1-tosyloxy-2,3-epoxypropane (202 mg) in drytetrahydrofuran (1 ml) were added below −50° C. The reaction mixture wasworked up in a usual manner and purified by a column chromatography(SiO₂ 40 cm³, 25% ethyl acetate-hexane) to give(R)-4-(3-toluenesulfonyloxy-2-hydroxy)propyl-1-benzyloxybenzene (144 mg)as an oil.

IR (Film) 1512, 1360, 1240, 1178, 978, 833, 814 cm⁻¹

NMR (CDCl₃, δ): 2.04 (1H, d, J=4.4 Hz), 2.45 (3H, s), 2.72 (2H, d, J=5.3Hz), 3.9-4.1 (3H, m), 5.04 (2H, s), 6.89 (2H, d, J=8.7 Hz), 7.06 (2H, d,J=8.7 Hz), 7.3-7.5 (7H, m), 7.7-7.9 (3H, m)

Preparation 76

A mixture of(R)-1-(3-toluenesulfonyloxy-2-hydroxy)propyl-3-nitro-4-benzyloxybenzene(26 mg), iron powder, ammonium chloride (2.6 mg) and wet ethanol (0.5ml) was heated at 80° C. for 1 hour and 20 minutes, filtered and workedup in the usual manner. The residue was treated with small amounts ofpotassium carbonate in methanol and worked up in the usual manner togive epoxide. The crude epoxide was dissolved in dichloromethane,treated with triethylamine followed by methanesulfonyl chloride, workedup in the usual manner and purified by preparative TLC (SiO₂, 50% ethylacetate-hexane) to give(R)-1-(3-methanesulfonylamino-4-benzyloxy)phenyl-2,3-epoxypropane (10.8mg) as an oil.

IR (Film) 2931, 1612, 1508, 1365, 1321, 1270, 1160, 975, 924 cm⁻¹

NMR (CDCl₃, δ): 2.50 (1H, dd, J=2.6 and 4.9 Hz), 2.7-3.0 (3H, m), 2.89(3H, s), 3.1-3.2 (1H, m), 5.14 (2H, s), 7.02 (1H, d, J=8.4 Hz), 7.24(1H, dd, J=2.2 and 9.6 Hz), 7.3-7.6 (6H, m)

Preparation 77

Under nitrogen, to a solution of 4-acetylaminophenol (569 mg) and sodiumhydride (150 mg) in N,N-dimethylformamide (30 ml) was added(2S)-(+)-1-tosyloxy-2,3-epoxypropane (1.0 g) at 0° C., and the mixturewas stirred at the same temperature for 0.5 hour. The mixture wasallowed to warm to room temperature and stirred for 3 hours at thistemperature. The resulting mixture was poured into 10% aqueous ammoniumchloride solution and extracted with ethyl acetate. The organic layerwas washed with brine, dried over magnesium sulfate and evaporated invacuo. The residue was chromatographed (hexane-ethyl acetate) oversilica gel to afford (2S)-1-(4-acetylamino)phenoxy-2,3-epoxypropane (285mg).

(+) APCI-MASS (m/z): 149 (M+Na)⁺

Preparation 78

Under nitrogen, to a solution of 2,3-dimethylbenzene-1,4-diol (25.0 g)and potassium hydroxide (40.6 g) in dimethylsulfoxide (100 ml) was addediodomethane (17 ml) at room temperature, and the mixture was stirred for3 hours at this temperature. The resulting mixture was poured into waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate and evaporated in vacuo to afford1,4-dimethoxy-2,3-dimethylbenzene (23.16 g).

(+) APCI-MASS (m/z): 167 (M+H)⁺

Preparation 79

A solution of 1,4-dimethoxy-2,3-dimethylbenzene (23.16 g), benzoylperoxide (673 mg) and N-bromosuccinimide (52.0 g) in carbontetrachloride(140 ml) was refluxed for 4 hours and filtered. The filtrate wasevaporated in vacuo. The residue was chromatographed (hexane-ethylacetate) over silica gel to afford2,3-dibromomethyl-1,4-dimethoxybenzene (8.17 g).

(+) APCI-MASS (m/z): 325 (M+H)⁺

Preparation 80

To a solution of N-isopropylcyclohexylamine (3.52 ml) in tetrahydrofuran(10 ml) was added 1M n-butyllithium in hexane (13.8 ml). After beingstirred for 20 minutes at this temperature, the solution was treateddropwise with tert-butyl acetate (2.96 ml). And after stirred for 20minutes, a solution of 2,3-dibromomethyl-1,4-dimethoxybenzene (2.73 g)in tetrahydrofuran (10 ml) was added below −68° C. After all had beenintroduced, the mixture was allowed to warm to −23° C. and stirred for2.5 hours at this temperature. The resulting mixture was added dropwiseto 1N hydrochloric acid (10 ml) with stirring under ice-cooling over 30minutes and extracted with ethyl acetate. The organic layer was washedwith brine, dried over magnesium sulfate and evaporated in vacuo. Theresidue was chromatographed (hexane-ethyl acetate) over silica gel toafford 3-[2-(2-tert-butoxycarbonylethyl)-3,6-dimethoxyphenyl]propionicacid tert-butyl ester (2.69 g).

NMR (CDCl₃, δ): 1.47 (18H, s), 2.29-2.43 (4H, m), 2.88-2.96 (4H, m),3.75 (6H, s), 6.66 (2H, s)

Preparation 81

3-[2-(2-tert-butoxycarbonylethyl)-3,6-dimethoxyphenyl]-propionic acidtert-butyl ester (6.33 g) was added dropwise to a refluxed solution ofsodium hydride (578 mg) in dry toluene (60 ml) and dry tert-butylalcohol (0.5 ml), and stirred for 3 hours. After cooling, to thereaction mixture glacial acetic acid was added dropwise followed byaddition of ice water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over magnesium sulfate and evaporatedin vacuo. To the residue were added methanol (50 ml) and 6N hydrochloricacid (15 ml), and this mixture was refluxed for 3 hours, poured into iceand extracted with ethyl acetate. The residue was chromatographed(hexane-ethyl acetate) over silica gel to afford1,4-dimethoxy-5,6,8,9-tetrahydrobenzocyclohepten-7-one (2.99 g).

MASS (m/z): 221 (M+H)⁺

Preparation 82

A solution of 1,4-dimethoxy-5,6,8,9-tetrahydrobenzo-cyclohepten-7-one(670 mg) and benzylamine (0.5 ml) in toluene (60 ml) in the presence ofa catalytic amount of p-toluenesulfonic acid monohydrate was refluxedfor 2 hours to remove water as the toluene azeotrope, and then themixture was evaporated in vacuo. To the residue in methanol (60 ml) wasadded sodium borohydride (0.5 g) under nitrogen at 5° C., and themixture was stirred at room temperature for 12 hours. The resultingmixture was poured into ice-cold water and stirred for 30 minutes beforeadding ethyl acetate and brine. After separation, the organic layer waswashed with brine, dried over anhydrous magnesium sulfate and evaporatedin vacuo. The residue was chromatographed (hexane-ethylacetate-methanol) over silica gel to affordN-benzyl-(1,4-dimethoxy-5,6,8,9-tetrahydrobenzcyclohepten-7-yl)amine(600 mg).

MASS (m/z): 312 (M+H)⁺

Preparation 83

Under nitrogen, to fuming nitric acid (60 ml) was added6,7,8,9-tetrahydrobenzocyclohepten-5-one (20 g) on ice-cooling, and themixture was stirred at the same temperature for 1 hour. The resultingmixture was poured into ice water (200 ml). The precipitates werecollected by filtration and dissolved into ethyl acetate. The organiclayer was washed with brine, dried over magnesium sulfate and evaporatedin vacuo to afford 3-nitro-6,7,8,9-tetrahydrobenzocyclohepten-5-one(14.87 g).

(+) APCI-MASS (m/z): 228 (M+Na)⁺

Preparation 84

A mixture of 3-nitro-6,7,8,9-tetrahydrobenzocyclohepten-5-one (14.87 g),iron (14.87 g) and ammonium chloride (2.0 g) in ethanol (200 ml) andwater (40 ml) was refluxed for 5 hours, and filtered. The filtrate wasevaporated in vacuo to afford3-amino-6,7,8,9-tetrahydrobenzocyclohepten-5-one (12.86 g).

NMR (CDCl₃, δ) 1.75-1.90 (4H, m), 2.60-2.90 (6H, m), 6.73-7.07 (3H, m)

Preparation 85

To a solution of 3-amino-6,7,8,9-tetrahydrobenzocyclohepten-5-one (12.53g) in 10% sulfuric acid (130 ml) was added sodium nitrite (4.9 g) andsodium sulfite (694 mg) under ice-cooling. After being stirred for 20minutes at this temperature, to the reaction mixture was added toluene(100 ml), stirred at the room temperature for 18 hours and extractedwith ethyl acetate. The organic layer was washed with brine, dried overmagnesium sulfate and evaporated in vacuo to afford3-hydroxy-6,7,8,9-tetrahydrobenzocyclohepten-5-one (7.08 g).

(+) APCI-MASS (m/z): 177 (M+H)⁺

Preparation 86

A mixture of 3-hydroxy-6,7,8,9-tetrahydrobenzocyclohepten-5-one (7.02g), potassium carbonate (8.25 g) and iodomethane (7.4 ml) inN,N-dimethylformamide (70 ml) was stirred at 50-55° C. for 7 hours. Theresulting mixture was diluted with ethyl acetate. The organic layer waswashed with brine, dried over magnesium sulfate and evaporated in vacuoto afford 3-methoxy-6,7,8,9-tetrahydrobenzocyclohepten-5-one (5.49 g).

(+) APCI-MASS (m/z): 191 (M+H)⁺

Preparation 87

A solution of 3-methoxy-6,7,8,9-tetrahydrobenzocyclohepten-hepten-5-one(6.0 g) and benzylamine (3.4 ml) in toluene (60 ml) in the presence of acatalytic amount of p-toluenesulfonic acid monohydrate was refluxed for2 hours to remove water at the toluene azeotrope, and then the mixturewas evaporated in vacuo. To the residue in methanol (60 ml) was addedsodium borohydride (1.2 g) under nitrogen at 5° C., and the mixture wasstirred at room temperature for 12 hours. The resulting mixture waspoured into ice-cold water and stirred for 30 minutes. After separation,the organic layer was washed with brine, dried over anhydrous magnesiumsulfate and evaporated in vacuo. The residue was chromatographed(hexane-ethyl acetate-methanol) over silica gel to affordN-benzyl-(1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(7.27 g).

(+) APCI-MASS (m/z): 282 (M+H)⁺

Preparation 88

Methanesulfonyl chloride (1.4 ml) was added dropwise to a solution ofacetic acid 3-amino-4-benzylphenyl ester (4.3 g) in pyridine (20 ml)under ice-cooling over 10 minutes, and the mixture was stirred at roomtemperature for a further 1 hour. Therein was added water (100 ml) andthe resulting mixture was stirred at the same temperature for 1 hour.The precipitates were collected by filtration, dissolved into chloroform(100 ml), followed by its dryness over magnesium sulfate and itsevaporation in vacuo. The residue was chromatographed (hexane-ethylacetate) over silica gel to afford acetic acid4-benzyloxy-3-methanesulfonylaminophenyl ester (1.6 g).

NMR (CDCl₃δ): 2.27 (3H, s), 2.95 (3H, s), 5.09 (2H, s), 6.80-7.03 (3H,m), 7.25-7.45 (6H, m)

(+) APCI-MASS (m/z): 336 (M+H)⁺

Preparation 89

A solution of acetic acid 4-benzyloxy-3-methanesulfonylaminophenyl ester(1.6 g) and potassium hydride (2.67 g) in methanol (10 ml) was stirredfor 18 hours at room temperature. The reaction mixture was acidifiedwith 1N hydrochloric acid to pH 5-7 and extracted with ethyl acetate.The extract was washed with brine, dried over magnesium sulfate, andevaporated in vacuo. The residue was chromatographed (hexane-ethylacetate) over silica gel to affordN-(2-benzyloxy-5-hydroxyphenyl)methanesulfonamide (750 mg).

NMR (CDCl₃, δ): 2.90 (3H, s), 5.04 (2H, s), 6.58 (1H, dd, J=2.9 and 8.8Hz), 6.80-6.90 (2H, m), 7.09 (1H, d, J=2.9 Hz), 7.30-7.50 (6H, m)

(+) APCI-MASS (m/z): 294 (M+H)⁺

Preparation 90

Under nitrogen, to a solution ofN-(2-benzyloxy-5-hydroxyphenyl)methanesulfonamide (740 mg) and sodiumhydride (92.4 mg) in N,N-dimethylformamide (30 ml) was added(2S)-(+)-1-tosyloxy-2,3-epoxypropane (616 mg) at 0° C. and the mixturewas stirred at the same temperature for 0.5 hour. The mixture wasallowed to warm to room temperature and stirred for 2.5 hours at thistemperature. The resulting mixture was poured into 10% aqueous ammoniumchloride solution and extracted with ethyl acetate. The extract waswashed with brine, dried over magnesium sulfate and evaporated in vacuo.The residue was chromatographed (hexane-ethyl acetate) over silica gelto afford(2S)-1-(4-benzyloxy-3-methanesulfonylamino)phenoxy-2,3-epoxypropane (440mg).

NMR (CDCl₃, δ): 2.75 (1H, dd, J=2.7 and 4.9 Hz), 2.84-2.95 (4H, m),3.30-3.37 (1H, m), 3.90 (1H, dd, J=5.8 and 11.1 Hz), 4.07-4.25 (1H, m),5.05 (2H, s), 6.63-7.48 (9H, m)

(+) APCI-MASS (m/z): 350 (M+H)⁺

Preparation 91

To a solution of2-[8-[(2S)-2-hydroxy-3-phenoxypropylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid ethyl ester (3.29 g) and triethylamine (2.55 ml) in tetrahydrofuran(20 ml) was added di-tert-butyl dicarbonate (1.53 g) under ice-cooling,and the mixture was stirred at room temperature for 18 hours. Theresulting mixture was poured into saturated aqueous sodium bicarbonatesolution and extracted with ethyl acetate. The organic layer was washedwith brine, dried over magnesium sulfate and evaporated in vacuo. Theresidue was chromatographed (hexane-ethyl acetate) over silica gel toafford 2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid ethyl ester (3.61 g).

NMR (CDCl₃, δ): 1.30 (3H, t, J=9.1 Hz), 1.49 (9H, s), 1.50-2.05 (4H, m),1.60-1.80 (3H, m), 3.20-3.80 (4H, m), 3.90-4.20 (3H, m), 4.27 (2H, q,J=7.1 Hz), 4.57 (1H, s), 6.60-6.70 (2H, s), 6.90-7.05 (4H, m), 7.10-7.38(2H, m)

Preparation 92

To a solution of 2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid ethyl ester (3.60 g) in ethanol (20 ml) was added 1N sodiumhydroxide (7 ml) under ice-cooling, and the mixture was stirred at roomtemperature for 2 hours. The resulting mixture was acidified withhydrochloric acid to pH 2 and extracted with ethyl acetate. The organiclayer was washed with brine, dried over magnesium sulfate and evaporatedin vacuo. The residue was chromatographed (hexane-ethyl acetate) oversilica gel to afford2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid (3.2 g).

NMR (CDCl₃, δ): 1.49 (9H, s), 1.90-2.05 (4H, m), 2.60-2.80 (3H, m),3.20-3.75 (4H, m), 3.80-4.30 (3H, m), 4.61 (2H, s), 6.60-6.75 (2H, m),6.80-7.05 (4H, m), 7.20-7.40 (2H, m)

Preparation 93

Under nitrogen, to a solution ofN-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(300 mg) and 1-[N-phenyl-N-benzyloxycarbonylamino]-2,3-epoxypropane (300mg) in dichloromethane (5 ml) was added ytterbium(III)trifluoromethanesulfonate (66 mg) at room temperature, and the mixturewas stirred at the same temperature for 24 hours. The resulting mixturewas poured into saturated aqueous sodium hydrogencarbonate and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and evaporated in vacuo. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=10:1 to 4:1) to giveN-[3-[N′-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-2-hydroxypropyl[-N-benzyloxycarbonylphenylamine(307 mg).

(+) APCI-MASS (m/z): 565 (M+H)⁺

EXAMPLE 1

Under nitrogen, to a solution ofN-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(487 mg) and (2S)-3-phenoxy-1,2,-epoxypropane (338 mg) indichloromethane (10 ml) was added ytterbium(III)trifluoromethanesulfonate (107 mg) at room temperature, and the mixturewas stirred at the same temperature for 3 hours. The resulting mixturewas poured into saturated aqueous sodium bicarbonate solution, andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate, and evaporated in vacuo. The residue waschromatographed (hexane-ethyl acetate) over silica gel to afford(2S)-1-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol(750 mg).

NMR (CHCl₃, δ): 1.22-2.15 (4H, m), 2.45-3.10 (6H, m), 3.32-3.39 (1H, m),3.70-4.10 (7H, m), 4.20-4.25 (1H, m), 6.58-7.00 (7H, m), 7.20-7.45 (6H,m)

MASS (m/z): 432 (M+H)⁺

The following compounds [Example 2 to 4] were obtained according to asimilar manner to that of Example 1.

EXAMPLE 2

(2S)-1-[N-Benzyl-N-(1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol

NMR (CHCl₃, δ): 1.10-2.35 (5H, m), 2.50-3.15 (6H, m), 3.32-3.48 (1H, m),3.64-3.98 (5H, m), 3.77 (3H, s), 6.69-7.09 (6H, m), 7.18-7.32 (7H, m)

MASS (m/z): 432 (M+H)⁺

EXAMPLE 3

2-[8-[N′-Benzyl-(2-hydroxy-3-phenoxypropyl)amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-phenylacetamide

NMR (CDCl₃, δ): 1.22-2.33 (4H, m), 2.53-3.18 (7H, m), 3.67-4.05 (5H, m),4.55-4.63 (2H, m), 6.65-6.78 (1H, m), 6.78-7.05 (5H, m), 7.05-7.47 (10H,m), 7.60 (2H, d, J=8.5 Hz)

MASS (m/z): 551 (M+H)⁺

EXAMPLE 4

2-[8-[N′-Benzyl-(2-hydroxy-3-phenoxypropyl)amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-butylacetamide

NMR (CDCl₃, δ): 0.92 (3H, t, J=7.4 Hz), 1.15-2.30 (8H, m), 2.50-2.95(6H, m), 2.98-3.15 (1H, m), 3.35 (2H, q, J=6.7 Hz), 3.63-4.01 (5H, m),4.41-4.50 (2H, m), 6.47-7.03 (7H, m), 7.15-7.45 (7H, m)

MASS (m/z): 531 (M+H)⁺

EXAMPLE 5

N-Benzyl-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)aminehydrochloride was converted to the corresponding free base in a usualmanner. A mixture of (2S)-3-phenoxy-1,2-epoxypropane (75 mg),N-benzyl-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amine(140 mg), and ytterbium(III) trifluoromethanesulfonate (93 mg) intoluene (2.6 ml) was stirred at room temperature for 3 days andpartitioned between ethyl acetate and aqueous sodium bicarbonate. Theorganic layer was separated, washed with brine, dried over sodiumsulfate, and evaporated in vacuo. The residue was chromatographed(dichloromethane-methanol) over silica gel to afford(2S)-1-[N-benzyl-N-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol(200 mg).

IR (KBr): 3427, 1248 cm⁻¹

NMR (CDCl₃, δ): 1.25-2.25 (4H, m), 2.5-3.02 (7H, m), 3.65-4.0 (8H, m),6.63 (2H, m), 6.83-6.98 (3H, m), 7.03-7.08 (1H, m), 7.18-7.31 (7H, m)

MASS (m/z): 432 (M+H)⁺

EXAMPLE 6

A mixture of(2S)-1-[N-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol(750 mg) and 10% palladium on activated carbon (50% wet, 200 mg) inmethanol (10 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 3 hours, and filtered. Thefiltrate was evaporated in vacuo and treated with 4N hydrogenchloride inethyl acetate to afford(2S)-1-[(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanolhydrochloride (446 mg).

NMR (DMSO-d₆, δ): 1.09-1.30 (1H, m), 1.80-2.10 (2H, m), 2.25-2.34 (1H,m), 2.55-2.70 (2H, m), 3.00-3.70 (5H, m), 3.73 (3H, s), 4.01 (2H, d,J=4.0 Hz), 4.20-4.30 (1H, m), 5.94 (1H, br s), 6.71 (1H, dd, J=2.6 and8.2 Hz), 6.83 (1H, dd, J=2.7 and 6.2 Hz), 6.87-7.08 (4H, m), 7.23-7.36(2H, m), 8.90 (1H, br s), 8.29 (1H, br s)

MASS (m/z): 342 (M+H)⁺

The following compounds [Example 7 and 8] were obtained according to asimilar manner to that of Example 6.

EXAMPLE 7

(2S)-1-[(2-Methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanolhydrochloride

IR (KBr): 3423, 2800-2350, 1246 cm⁻¹

NMR (DMSO-d₆, δ): 1.35 (1H, m), 1.75-2.05 (2H, m), 2.25-2.35 (1H, m),2.70 (2H, m), 2.95-3.35 (5H, m), 3.71 (3H, s), 4.01 (2H, m), 4.24 (1H,m), 5.91 (1H, d, J=4.8 Hz), 6.66-6.73 (2H, m), 6.92-6.70 (3H, m), 7.12(1H, dd, J=8.0 and 2.5 Hz), 7.31 (2H, t, J=7.8 Hz), 8.78 (1H, br), 9.07(1H, br)

MASS (m/z): 342 (M+H)⁺

EXAMPLE 8

(2S)-1-[(1-Methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanolhydrochloride

NMR (DMSO-d₆, δ): 1.04-1.32 (1H, m), 1.75-2.11 (2H, m), 2.23-2.40 (1H,m), 2.96-3.49 (7H, m), 3.75 (3H, s), 3.96-4.03 (2H, m), 4.26 (1H, br s),5.92 (1H, br s), 6.81-7.01 (5H, m), 7.11 (1H, t, J=7.7 Hz), 7.31 (2H, t,J=7.7 Hz), 8.88 (1H, br s), 9.25 (1H, br s)

MASS (m/z): 342 (M+H)⁺

EXAMPLE 9

A mixture of 2-[8-[N′-benzyl-(2-hydroxy-3-phenoxypropyl)amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-phenylacetamide(360 mg) and 10% palladium on activated carbon (50% wet, 70 mg) inethanol (5 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 4 hours and filtered. Thefiltrate was evaporated in vacuo. The residue was chromatographed(chloroform-methanol) over silica gel to afford2-[8-(2-hydroxy-3-phenoxypropylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-phenylacetamide(306 mg)

The above obtained compound (306 mg) was treated with methanesulfonicacid (43 μl) to afford2-[8-(2-hydroxy-3-phenoxypropylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-phenylacetamidemethanesulfonate (303 mg)

NMR (DMSO-d₆, δ): 1.18-1.43 (1H, m), 1.74-2.13 (2H, m), 2.18-2.37 (1H,m), 2.39 (3H, s), 2.60-2.83 (2H, m), 2.95-3.38 (5H, m), 3.95-4.40 (3H,m), 4.68 (2H, s), 6.78 (1H, d, J=8.0 Hz), 6.86-7.14 (6H, m), 7.32 (4H,t, J=7.6 Hz), 7.65 (2H, d, J=8.0 Hz), 8.59 (2H, br s), 10.11 (1H, s)

MASS (m/z): 461 (M+H)⁺

EXAMPLE 10

A mixture of2-[8-(N′-benzyl-(2-hydroxy-3-phenoxypropyl)amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-butylacetamide(206 mg) and 10% palladium on activated carbon (50% wet, 40 mg) inethanol (5 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 4 hours, and filtered. Thefiltrate was evaporated in vacuo. The residue was chromatographed(chloroform-methanol) over silica gel to afford2-[8-(2-hydroxy-3-phenoxypropylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-butylacetamide(171 mg).

The above obtained compound (70 mg) was treated with oxalic acid (14 mg)to afford2-[8-(2-hydroxy-3-phenoxypropylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-butylacetamideoxalate (28 mg)

NMR (DMSO-d₆, δ): 0.85 (3H, t, J=6.9 Hz), 1.10-1.50 (5H, m), 1.70-2.12(2H, m), 2.15-2.37 (1H, m), 2.60-2.78 (2H, m), 2.90-3.37 (7H, m), 3.99(2H, br s), 4.20 (1H, br s), 4.63 (2H, s), 6.72 (1H, d, J=8.0 Hz),6.77-7.10 (5H, m), 7.31 (2H, d, J=7.4 Hz)

MASS (m/z): 441 (M+H)⁺

EXAMPLE 11

A mixture of 4-oxiranylmethoxy-1,3-dihydro-2-benzimidazolone (82.5 mg)andN-benzyl-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amine(107 mg) in ethanol (1.5 ml) was stirred under reflux for 13 hours,cooled to room temperature and evaporated in vacuo. The residue waschromatographed (dichloromethane-methanol)by silica gel (4.2 g) toafford1-[N-benzyl-N-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amino]-3-(1,3-dihydro-2-benzoimidazolon-4-yloxy)-2-propanol (123 mg) asa colorless powder.

mp: 111-133° C. (dec.)

IR (KBr): 3408 (br), 3257 (br), 1695, 1248 cm⁻¹

NMR (DMSO-d₆, δ): 1.03-1.97 (4H, m), 2.22-2.84 (6H, m), 3.63-4.17 (6H,m, 4.60 and 4.67 (1H, each d, J=4.1 Hz), 6.43 (2H, m), 6.53-6.63 (2H,m), 6.79-6.95 (2H, m), 7.11-7.35 (5H, m), 8.99 (1H, s), 10.55 (2H, br s)

(+) APCI-MASS (m/z): 474 (M+H)⁺

EXAMPLE 12

A solution of (2S)-1,2-epoxy-3-phenoxypropane (53 mg) (IL FARMACO, 50(10), 643 (1995)) and N-benzyl-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amine(89 mg) in ethanol (1 ml) was refluxed for 19 hours, cooled to roomtemperature and evaporated in vacuo. The residue was chromatographed(dichloromethane-methanol) by silica gel (2.9 g), and the eluate wastreated with 4N hydrogen chloride in ethyl acetate to afford(2S)-1-[N-benzyl-N-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol hydrochloride (149 mg) as a colorlesspowder.

mp: 94-99° C. (dec.)

IR (KBr): 3421 (br), 2750-2450 (m), 1244 cm⁻¹

EXAMPLE 13

Under nitrogen, to a solution ofN-benzyl-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(258 mg) and (2S)-3-phenoxy-1,2-epoxypropane (138 mg) in dichloromethane(5 ml) was added ytterbium(III) trifluoromethanesulfonate (52 mg) atroom temperature, and the mixture was stirred at the same temperaturefor 60 hours. The resulting mixture was poured into saturated aqueoussodium hydrogencarbonate and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=10:1 to 5:1) to give(2S)-1-[N-benzyl-N-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-amino]-3-phenoxy-2-propanol(303 mg)

(+) APCI-MASS (m/z): 460 (M+H)⁺

The following compounds [Examples 14 to 27] were obtained according to asimilar manner to that of Example 13.

EXAMPLE 14

(2S)-1-[N-Benzyl-N-(3-hexyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol

(+) APCI-MASS (m/z): 502 (M+H)⁺

EXAMPLE 15

(2S)-1-[N-Benzyl-N-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol

(+) ESI-MASS (m/z): 508 (M+H)⁺

EXAMPLE 16

(2S)-1-[N-Benzyl-N-[3-(3-cyanopyridin-2-yloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]amino]-3-phenoxy-2-propanol

(+) APCI-MASS (m/z): 520 (M+H)⁺

EXAMPLE 17

(2S)-1-[N-Benzyl-N-[3-(2-methoxyethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)]amino]-3-phenoxy-2-propanol

(+) APCI-MASS (m/z): 476 (M+H)⁺

EXAMPLE 18

(2S)-1-[N-Benzyl-N-(3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol

(+) APCI-MASS (m/z): 447 (M+H)⁺

EXAMPLE 19

(2S)-1-(N-Benzyl-N-(6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol

(+) APCI-MASS (m/z): 402 (M+H)⁺

EXAMPLE 20

(2S)-1-[N-Benzyl-N-(3-phenyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol

(+) ESI-MASS (m/z): 478 (M+H)⁺

EXAMPLE 21

(2S)-1-[N-Benzyl-N-(2-chloro-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol

(+) ESI-MASS (m/z): 466, 468 (M+H)⁺

EXAMPLE 22

(2S)-1-[N-Benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenylthio-2-propanol

(+) APCI-MASS (m/z): 448 (M+H)⁺

EXAMPLE 23

(2S)-1-[N-Benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-(4-fluorophenoxy)-2-propanol

NMR (CDCl₃, δ): 0.85-1.25 (1H, m), 1.65-2.1 (2H, m), 2.2-2.4 (1H, m),2.45-2.95 (7H, m), 3.65-3.85 (7H, m), 3.85-4.1 (1H, m), 6.55-6.6 (1H,m), 6.65-6.75 (1H, m), 6.8-7.4 (10H, m)

(+) APCI-MASS (m/z): 450 (M+H)⁺

EXAMPLE 24

(2S)-1-[N-Benzyl-N-(6,7,8,9-tetrahydro-4-methoxy-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanolhydrochloride

NMR (DMSO-d₆, δ): 1.10-1.38 (1H, m), 1.97-2.20 (2H, m), 2.38-2.52 (1H,m), 2.60-3.00 (4H, m), 3.18-3.58 (3H, m), 3.70-4.02 (3H, m), 3.79 (3H,s), 4.45-4.64 (2H, m), 6.01 (1H, br), 6.70-6.99 (5H, m), 7.13 (1H, dd,J=8.0, 8.0 Hz), 7.30 (2H, dd, J=7.9, 7.9 Hz), 7.40-7.56 (3H, m),7.65-7.80 (2H, m), 9.42-10.09 (1H, br)

(+) ESI-MASS (m/z): 432 (M+H)⁺

EXAMPLE 25

(2S)-1-[N-Benzyl-N-(3-methoxycarbonyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanolhydrochloride

NMR (DMSO-d₆, δ): 1.10-1.33 (1H, m), 1.99-2.21 (2H, m), 2.40-2.55 (1H,m), 2.75-2.91 (2H, m), 3.04-3.17 (1H, m), 3.26-3.38 (3H, m), 3.45-3.59(2H, m), 3.70-4.01 (2H, m), 3.84 (3H, s), 4.39-4.69 (2H, m), 5.92-6.05(1H, br), 6.81-7.00 (3H, m), 7.23-7.34 (3H, m), 7.38-7.48 (3H, m),7.68-7.97 (4H, m), 9.67-9.95 (1H, br)

(+) ESI-MASS (m/z): 460 (M+H)⁺

EXAMPLE 26

(2S)-1-[N-Benzyl-N-(3-carbamoyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanolhydrochloride

NMR (DMSO-d₆, δ): 1.18-1.34 (1H, m), 2.00-2.20 (2H, m), 2.33-2.58 (1H,m), 2.78-2.90 (2H, m), 3.02-3.50 (5H, m), 3.72-4.02 (3H, m), 4.28-4.62(2H, m), 5.98 (1H, br), 6.80-6.98 (3H, m), 7.17-7.44 (7H, m), 7.63-7.91(5H, m), 9.36-9.92 (1H, br)

(+) APCI-MASS (m/z): 445 (M+H)⁺

EXAMPLE 27

1-[N-Benzyl-N-(3-methoxy-6,7,8,9-tetrahdyro-5H-benzocyclohepten-6-yl)amino]-4-phenyl-2-butanol

(+) APCI-MASS (m/z): 430 (M+H)⁺

EXAMPLE 28

Under nitrogen, to a solution ofN-(3-fluoromethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-tert-butoxycarbonyl-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-amine(300 mg) in tetrahydrofuran (5 ml) was added tetra-n-butylammoniumfluoride (1M in tetrahydrofuran, 0.58 ml) at 5° C., and the mixture wasstirred at the same temperature for 15 minutes. The resulting mixturewas poured into water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=3:1) to giveN-(3-fluoromethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-tert-butoxycarbonyl-[(2S)-2-hydroxy-3-phenoxypropyl]amine(227 mg).

NMR (CDCl₃, δ): 1.1-1.6 (1H, m), 1.49 (9H, s), 1.9-2.1 (3H, m),2.65-2.75 (3H, m), 3.15-3.7 (4H, m), 3.8-4.2 (3H, m), 5.67 (2H, d,J=54.8 Hz), 6.75-7.1 (5H, m), 7.25-7.3 (2H, m)

EXAMPLE 29

Under nitrogen, to a suspension of sodium hydride (60% in oil, 12 mg) inN,N-dimethylformamide (3 ml) was addedN-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-tert-butoxycarbonyl-[(2S)-3-phenoxy-2-(triethylsilyloxy)-propyl]amine(150 mg) at 5° C. After being stirred at the same temperature for 1.5hours, to this one was added dimethylsulfonyl chloride (31 μl), and themixture was stirred at 60° C. for 15 hours. The resulting mixture waspoured into saturated aqueous sodium hydrogencarbonate and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and evaporated in vacuo. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=3:1) to give (1):N-(3-dimethylsulfonyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-tert-butoxycarbonyl-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]amine(59 mg) and (2):N-(3-dimethylsulfonyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-tert-butoxycarbonyl-[(2S)-2-hydroxy-3-phenoxypropyl]-amine(66 mg).

(1): NMR (CDCl₃, δ): 0.55-0.7 (6H, m), 0.9-1.05 (9H, m), 0.2-1.5 (1H,m), 1.48 (9H, m), 1.9-2.15 (3H, m), 2.7-3.0 (3H, m), 2.95 (6H, m),3.1-3.7 (4H, m), 3.85-4.05 (2H, m), 4.3-4.4 (1H, m), 6.85-7.1 (6H, m),7.25-7.3 (2H, m)

(+) APCI-MASS (m/z): 549 (M-Boc+2H)⁺

(2): NMR (CDCl₆, δ): 0.55-0.7 (6H, m), 0.9-1.05 (9H, m), 1.2-1.5 (1H,m), 1.48 (9H, m), 1.9-2.15 (3H, m), 2.7-3.0 (3H, m), 2.95 (6H, m),3.1-3.7 (4H, m), 3.85-4.05 (2H, m), 4.3-4.4 (1H, m), 6.85-7.1 (6H, m),7.25-7.3 (2H, m)

(+) APCI-MASS (m/z): 435 (M-Boc+2H)⁺

EXAMPLE 30

Under nitrogen, to a solution of2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)acetamide(260 mg) and (2S)-3-phenoxy-1,2-epoxypropane (130 mg) in dichloromethane(3 ml) was added ytterbium(III) trifluoromethanesulfonate (50 mg) atroom temperature, and the mixture was stirred at the same temperaturefor 12 hours. The resulting mixture was poured into saturated aqueoussodium hydrogencarbonate and extracted with dichloromethane. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel (chloroform:ethyl acetate=20:1 to 10:1), followed bytreatment with methanesulfonic acid in chloroform to give2-[8-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamidemethanesulfonate (290 mg).

(+) APCI-MASS (m/z): 475 (M-MsOH+H)⁺

EXAMPLE 31

A solution of2-[8-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid ethyl ester (200 mg) and N,N-dimethylethylenediamine (130 μl) inmethanol (2 ml) was stirred at room temperature for 24 hours. Afterevaporation in vacuo, the residue was purified by preparative thin layerchromatography (silica gel, chloroform:methanol=10:1) to give2-[8-[N′-benzyl-N′-[(2S)-2-hydroxy-3-phenoxypropyl]-amino]6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-(2-dimethylaminoethyl)acetamide(215 mg).

(+) APCI-MASS (m/z): 546 (M+H)⁺

EXAMPLE 32

Under nitrogen, a solution of2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2yloxy]aceticacid (100 mg) in dichloromethane (3 ml) were added N-methylbutylamine(29 μl) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(47 mg) in the presence of catalytic amounts of 4-dimethylaminopyridineat 5° C., and the mixture was stirred at room temperature for 12 hours.The resulting mixture was poured into 1N hydrochloric acid and extractedwith ethyl acetate. The organic layer was successively washed withsaturated aqueous sodium hydrogencarbonate and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=1:1) to giveN-[3-[(butylmethylcarbamoyl)methoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-N-tert-butoxycarbonyl-[(2S)-2-hydroxy-3-phenoxypropyl]amine(96 mg).

NMR (CHCl₃, δ): 0.92 (3H, q, J=7.6 Hz), 1.18-1.70 (5H, m) , 1.49 (9H, s), 1.93-2.15 (3H, m), 2.59-2.82 (3H, m), 2.94-3.04 (3H, m), 3.20-3.66(6H, m), 3.83-4.25 (3H, m), 4.62-4.67 (2H, m,, 6.65-6.77 (2H, m),6.87-7.02 (4H, m), 7.25-7.34 (2H, m)

(+) APCI-MASS (m/z): 455 (M-Boc+2H)⁺

The following compounds[Examples 33 to 38] were obtained according to asimilar manner to that of Example 32.

EXAMPLE 33

N-[(2S)-2-Hydroxy-3-phenoxypropyl]-N-tert-butoxycarbonyl-[3-(sec-butylcarbamoylmethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]amine

(+) APCI-MASS (m/z): 441 (M-Boc+2H)⁺

EXAMPLE 34

N-(3-Cyclohexylcarbamoylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-tert-butoxycarbonyl-[(3S)-2-hydroxy-3-phenoxypropyl)amine

(+) APCI-MASS (m/z): 467 (M-Boc+2H)⁺

EXAMPLE 35

N-[3-(Benzylcarbamoylmethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-N-tert-butoxycarbonyl-[(2S)-2-hydroxy-3-phenoxypropyl]amine

(+) APCI-MASS (m/z): 475 (M-Boc+2H)⁺

EXAMPLE 36

N-[(2S)-2-Hydroxy-3-phenoxypropyl]-N-tert-butoxycarbonyl-[3-[(2-methylthioethylcarbamoyl)methoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]amine

(+) APCI-MASS (m/z): 459 (M-Boc+2H) +

EXAMPLE 37

N-[(2S)-2-Hydroxy-3-phenoxypropyl)-N-tert-butoxycarbonyl-[3-(2-piperidinocarbonylethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]amine

(+) APCI-MASS (m/z): 453 (M-Boc+2H)⁺

EXAMPLE 38

N-[(2S)-2-Hydroxy-3-phenoxypropyl]-N-tert-butoxycarbonyl-[3-[(1H-indol-5-yl-carbamoyl)methoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]amine

NMR (CDCl₃, δ): 1.22-1.70 (1H, m), 1.50 (9H, s), 1.96-2.18 (3H, m),2.66-2.88 (3H, m), 3.26-3.70 (4H, m), 3.85-4.26 (3H, m), 4.59 (2H, s),6.51-6.56 (1H, m), 6.68-6.87 (2H, m), 6.88-7.09 (4H, m), 7.23-7.39 (6H,m), 7.92 (1H, m), 8.16-8.37 (2H, m)

(+) APCI-MASS (m/z): 500 (M-Boc+2H)⁺

EXAMPLE 39

A suspension of powdered iron (160 mg) and ammonium chloride (15 mg) ina mixture of ethanol (6 ml) and water (2 ml) was refluxed, and to thisone was dropwise added(2S)-1-[N-benzyl-N-(3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol(158 mg) in ethanol (3 ml). After being further refluxed for 1 hour,insoluble materials were filtered off. The filtrate was evaporated invacuo. The residue was dissolved into a mixture of saturated aqueoussodium hydrogencarbonate and ethyl acetate. After separation, theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=2:1 to 1:1) to give(2S)-1-[N-(3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol(122 mg).

(+) ESI-MASS (m/z): 417 (M+H) +

EXAMPLE 40

Under nitrogen, a solution of(2S)-1-[N-(3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol(200 mg), methyl iodide (0.15 ml) and N,N-diisopropylethylamine (0.25ml) in dichloromethane (5 ml) was stirred at room temperature for 12hours. The resulting mixture was poured into saturated aqueous sodiumhydrogencarbonate and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=4:1) to give a less polardiastereomer:(2S)-1-[N-benzyl-N-(3-dimethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol(28 mg) and a more polar diastereomer:(2S)-1-[N-benzyl-N-(3-dimethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol(25 mg).

A Less Polar Diastereomer

(+) APCI-MASS (m/z): 445 (M+H)⁺

A More Polar Diastereomer

(+) APCI-MASS (m/z): 445 (M+H)⁺

EXAMPLE 41

Under nitrogen, a solution of(2S)-1-[N-(3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol(113 mg), acetic anhydride (28 μl) and pyridine (24 μl) indichloromethane (5 ml) was stirred at 5° C. for 1 hour. The resultingmixture was poured into water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=1:1 to 1:2) to giveN-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]-3-acetylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (92 mg).

(+) APCI-MASS (m/z): 459 (M+H)⁺

EXAMPLE 42

Under nitrogen, a solution of(2S)-1-[N-(3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol(150 mg), benzoyl chloride (44 μl), pyridine (35 μl ), and catalyticamounts of 4-dimethylaminopyridine in dichloromethane (5 ml) was stirredat room temperature for 5 hours. The resulting mixture was poured intosaturated aqueous sodium hydrogencarbonate and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=2:1) to giveN-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]-3-benzoylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine(163 mg).

(+) APCI-MASS (m/z): 521 (M+H)⁺

EXAMPLE 43

Under nitrogen, a solution of(2S)-1-[N-(3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol(150 mg), methanesulfonyl chloride (29 μl), pyridine (35 μl), andcatalytic amounts of 4-dimethylaminopyridine in dichloromethane (5 ml)was stirred at room temperature for 4 hours. The resulting mixture waspoured into saturated aqueous sodium hydrogencarbonate and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and evaporated in vacuo. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=2:1) to giveN-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropylamino]-3-methylsulfonylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine(178 mg).

(+) APCI-MASS (m/z): 495 (M+H)⁺

The following compound was obtained according to a similar manner tothat of Example 43.

EXAMPLE 44

N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine

(+) ESI-MASS (m/z): 557 (M+H)⁺

EXAMPLE 45

Under nitrogen, a solution of(2S)-1-(N-(3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol(150 mg), methyl chloroformate (29 μl), pyridine (25 μl) and catalyticamounts of 4-dimethylaminopyridine in dichloromethane (3 ml) was stirredat room temperature for 1.5 hours. The resulting mixture was poured intosaturated aqueous sodium hydrogencarbonate and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=3:1) to give(2S)-1-[N-(3-methoxycarbonylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol(158 mg).

(+) APCI-MASS (m/z): 475 (M+H)⁺

The following compound was obtained according to a similar manner tothat of Example 46.

EXAMPLE 46

(2S)-1-[N-(3-phenoxycarbonylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol

(+) APCI-MASS (m/z): 537 (M+H)⁺

EXAMPLE 47

Under nitrogen, a solution of(2S)-1-[N-(3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol(150 mg), dimethylaminosulfonyl chloride (43 μl) and pyridine (31 μl)intoluent (5 ml) was stirred at 80° C. for 24 hours. The resulting mixturewas poured into saturated aqueous sodium hydrogencarbonate and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and evaporated in vacuo. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=2:1) to give(2S)-1-[N-(3-dimethylaminosulfonylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol(156 mg).

(+) APCI-MASS (m/z): 524 (M+H)⁺

The following compound was obtained according to a similar manner tothat of Example 47.

EXAMPLE 48

(2S)-1-[N-(3-Sulfamoylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol

(+) APCI-MASS (m/z): 496 (M+H)⁺

EXAMPLE 49

To a solution of(2S)-1-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenylthio-2-propanol(221 mg) in methanol (10 ml) was added OXONE (610 mg) in water (3 ml) atroom temperature, and the mixture was stirred at the same temperaturefor 5 hours. The resulting mixture was filtered off to removeprecipitates and the filtrate was evaporated in vacuo. The residue wasdissolved into a mixture of saturated aqueous sodium hydrogencarbonateand ethyl acetate. After separation, the organic layer was washed withbrine, dried over anhydrous magnesium sulfate and evaporated in vacuo.The residue was purified by column chromatography on silica gel(hexane:ethyl acetate=2:1) to give(2S)-1-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenylsulfonyl-2-propanol(170 mg).

(+) APCI-MASS (m/z): 480 (M+H)⁺

EXAMPLE 50

A mixture ofN-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(200 mg) and 10% palladium on activated carbon (50% wet, 50 mg) inmethanol (5 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 3 hours. After filtration, thefiltrate was evaporated in vacuo. A mixture of the residue and[5-[(2S)-oxiranyl)methoxypyridin-2-yl]carbamic acid benzyl ester (174mg) in methanol (10 ml) was refluxed for 20 hours. After removal of thesolvent in vacuo, the residue was purified by column chromatography onsilica gel (chloroform:methanol=50:1 to 20:1) to giveN-[5-[(2S)-2-hydroxy-3-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)propoxy]pyridin-2-yl]benzyloxycarbonylamine(200 mg).

(+) APCI-MASS (m/z): 492 (M+H)⁺

The following compound was obtained according to a similar manner tothat of Example 50.

EXAMPLE 51

4-[2-Hydroxy-3-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)propoxy]-1,3-dihydrobenzimidazol-2-onehydrochloride

(+) APCI-MASS (m/z): 398 (M-HCl +H)⁺

EXAMPLE 52

8-[[(2S)-2-Hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylicacid methyl ester hydrochloride (8.40 g) was converted to thecorresponding free base in a usual manner. The free base was dissolvedin tetrahydrofuran (60 ml), and a solution of di-tert-butyl dicarbonate(4.52 g) in tetrahydrofuran (10 ml) was added to the mixture. Afterstirring overnight, the reaction mixture was evaporated in vacuo, andthe residue was purified by column chromatography on silica gel elutingwith a mixture of hexane and ethyl acetate (5:1 to 3:1) to afford8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]-amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylicacid methyl ester (9.88 g).

NMR (DMSO-d₆, δ): 1.15-1.40 (1H, m), 1.41 (9H, s), 1.86-2.35 (3H, m),2.68-3.60 (7H, m), 3.83 (3H, s), 3.85-4.08 (3H, m), 5.19 (1H, d, J=5.1Hz), 6.89-6.99 (3H, m), 7.22-7.33 (3H, m), 7.70 (1H, dd, J=7.7 and 1.6Hz), 7.75 (1H, s)

(+) ESI-MASS (m/z): 492 (M+Na)⁺

EXAMPLE 53

To a solution of8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylicacid methyl ester (4.5 g) in methanol (45 ml) and tetrahydrofuran (15ml) was added 1N sodium hydroxide aqueous solution. After stirring atroom temperature for 6 hours, the reaction mixture was concentratedunder reduced pressure, neutralized with 1N hydrochloric acid solutionunder ice-cooling. The product was extracted with ethyl acetate, and theorganic layer was washed with brine, dried over magnesium sulfate andevaporated in vacuo to afford8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylicacid (4.48 g).

NMR (DMSO-d₆, δ): 1.19-1.40 (1H, m), 1.41 (9H, s), 1.89-2.37 (3H, m),2.71-3.58 (7H, m), 3.80-4.03 (3H, m), 5.17 (1H, d, J=5.0 Hz), 6.88-6.95(3H, m), 7.19-7.32 (3H, m), 7.67 (1H, d, J=7.7 Hz), 7.74 (1H, s)

(+) APCI-MASS (m/z): 356 (M-Boc+2H)⁺

EXAMPLE 54

To a mixture of8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylicacid (0.30 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.15 g) and 1-hydroxybenzotriazole (0.11 g) indichloromethane (6 ml) was added a solution of methylamine intetrahydrofuran (2.0M, 0.40 ml). The reaction mixture was stirred atroom temperature overnight, and partitioned between ethyl acetate andaqueous sodium bicarbonate solution. The organic layer was separated,washed with brine, dried over magnesium sulfate and evaporated in vacuo.The residue was purified by column chromatography on silica gel elutingwith a mixture of chloroform and methanol (100:1 to 10:1) to affordN-[(2S)-2-hydroxy-3-phenoxypropyl]-N-tert-butoxycarbonyl-(3-methylcarbamoyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(0.13 g).

NMR (DMSO-d₆, δ): 1.16-1.35 (1H, m), 1.40 (9H, s), 1.87-2.24 (3H, m),2.76 (3H, d, J=4.6 Hz), 2.70-2.92 (2H, m), 3.03-3.56 (5H, m), 3.85-4.02(3H, m), 5.14 (1H, d, J=5.1 Hz), 6.89-6.95 (3H, m), 7.15 (1H, d, J=7.7Hz), 7.28 (2H, dd, J=7.7 and 7.7 Hz), 7.55 (1H, d, J=7.7 Hz), 7.63 (1H,s), 8.28 (1H, t-like, J=4.6 Hz)

(+) ESI-MASS (m/z): 491 (M+Na)⁺

The following compounds [Examples 55 and 56] were obtained according toa similar manner to that of Example 54.

EXAMPLE 55

N-[(2S)-2-Hydroxy-3-phenoxypropyl]-N-tert-butoxycarbonyl-(3-dimethylcarbamoyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine

NMR (DMSO-d₆, δ): 1.19-1.38 (1H, m), 1.40 (9H, s), 1.90-2.08 (2H, m),2.12-2.30 (1H, m), 2.68-3.10 (4H, m), 2.93 (6H, s), 3.18-3.60 (3H, m),3.85-4.08 (3H, m), 5.16 (1H, br), 6.88-6.95 (3H, m), 7.12-7.17 (3H, m),7.28 (2H, dd, J=8.0 and 8.0 Hz)

(+) ESI-MASS (m/z): 505 (M+Na)⁺

EXAMPLE 56

N-[(2S)-2-Hydroxy-3-phenoxypropyl]-N-tert-butoxycarbonyl-(3-phenylcarbamoyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine

NMR (DMSO-d₆, δ): 1.19-1.20 (1H, m), 1.41 (9H, s), 1.88-2.36 (3H, m),2.75-3.60 (7H, m, 3.85-4.10 (3H, m), 5.19 (1H, d, J=5.0 Hz), 6.85-6.93(3H, m), 7.09 (1H, dd, J=7.4 and 7.4 Hz), 7.22-7.39 (5H, m), 7.64-7.78(4H, m), 10.11 (1H, s)

(+) ESI-MASS (m/z): 553 (M+Na)⁺

EXAMPLE 57

To a solution of8-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxamide(3.00 g) in dry tetrahydrofuran (90 ml) was gradually added lithiumaluminum hydride (1.02 g) under ice-cooling and nitrogen atmosphere. Themixture was then heated to reflux for 3 hours. Saturated sodiumbicarbonate solution was added dropwise to the reaction mixture underice-cooling, and the resulting precipitate was filtered off and washedwith ethyl acetate. The filtrate was extracted with ethyl acetate, andthe organic layer was washed with water and brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel eluting with a mixture of chloroform andmethanol (30:1 to 5:1) to afford(2S)-1-[N-(3-aminomethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol(2.75 g).

NMR (DMSO-d₆, δ): 1.00-1.20 (1H, m), 1.67-2.10 (3H, m) , 2.23-2.40 (1H,m) , 2.50-3.10 (8H, m) , 3.62 (2H, d, J=3.0 Hz), 3.70-3.86 (4H, m),3.92-4.02 (1H, m), 4.78 (1H, br), 6.83-7.00 (5H, m), 7.05-7.38 (8H, m)

(+) APCI-MASS (m/z): 431 (M+H)⁺

EXAMPLE 58

To a mixture of(2S)-1-[N-(3-aminomethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol(0.30 g) and triethylamine (0.107 ml) in dichloromethane (6 ml) wasadded dropwise acetyl chloride (0.05 ml) under ice-cooling. The mixturewas stirred at room temperature overnight and partitioned between waterand ethyl acetate. The organic layer was separated, washed with waterand brine, dried over magnesium sulfate and evaporated in vacuo. Theresidue was purified by column chromatography on silica gel eluting witha mixture of chloroform and methanol (50:1). The product was treatedwith 4N hydrogen chloride in ethyl acetate and powdered from diisopropylether to affordN-6-[N′-benzyl-N′-(2S)-2-hydroxy-3-phenoxypropyl)amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-3-ylmethyl]acetamide(0.29 g).

NMR (DMSO-d₆, δ): 1.09-1.30 (1H, m), 1.86-1.90 (total 3H, s), 1.98-2.18(2H, m), 2.38-2.62 (1H, m), 2.70-2.82 (2H, m), 3.03-3.68 (5H, m),3.74-4.04 (3H, m), 4.10-4.24 (2H, m), 4.40-4.68 (2H, m), 6.01 (1H, br),6.83-7.10 (6H, m), 7.24-7.34 (2H, m), 7.40-7.52 (3H, m), 7.65-7.82 (2H,m), 8.37 (1H, t, J=6.0 Hz), 9.68-10.24 (1H, br)

(+) APCI-MASS (m/z): 473 (M+H)⁺

The following compounds [Example 59 to 61] were obtained according to asimilar manner to that of Example 58.

EXAMPLE 59

N-[8-[N′-Benzyl-N′-[(2S)-2-hydroxy-3-phenoxypropyl]-amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethyl]-benzamidehydrochloride

NMR (DMSO-d₆, δ): 1.09-1.28 (1H, m), 1.93-2.19 (2H, m), 2.40-2.60 (1H,m), 2.67-2.84 (2H, m), 2.98-3.50 (5H, m), 3.74-4.02 (3H, m), 4.32-4.56(4H, m), 6.00 (1H, br), 6.83-6.98 (3H, m), 7.07-7.53 (11H, m), 7.66-7.78(2H, m), 7.94 (2H, dd, J=8.3 and 8.3 Hz), 9.12 (1H, t, J=6.0 Hz),9.81-10.38 (1H, br)

(+) APCI-MASS (m/z) 535 (M+H)⁺

EXAMPLE 60

N-[8-[N′-Benzyl-[N′-(2S)-2-hydroxy-3-phenoxypropyl]-amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethyl]-methanesulfonamidehydrochloride

NMR (DMSO-d₆, δ): 1.08-1.23 (1H, m), 1.97-2.18 (2H, m), 2.39-2.60 (1H,m), 2.66-2.80 (2H, m), 2.82, 2.89 (total 3H, s), 3.00-3.64 (5H, m),3.74-4.13 (5H, m), 4.40-4.70 (2H, m), 5.95 (1H, br), 6.83-6.98 (3H, m),7.09-7.60 (9H, m), 7.67-7.78 (2H, m), 9.73-10.36 (1H, br)

(+) APCI-MASS (m/z): 509 (M+H)⁺

EXAMPLE 61

N-[8-[N′-Benzyl-N′-[(2S)-2-hydroxy-3-phenoxypropyl]-amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethyl]-benzenesulfonamidehydrochloride

NMR (DMSO-d₆, δ): 1.05-1.23 (1H, m), 1.96-2.18 (2H, m), 2.41-2.85 (3H,m), 2.99-3.48 (5H, m), 3.70-4.03 (5H, m), 4.45-4.70 (2H, m), 5.98-6.06(1H, br), 6.83-7.06 (5H, m), 7.23-7.34 (3H, m), 7.40-7.84 (10H, m),8.12-8.22 (1H, m), 9.71-10.31 (1H, br)

(+) APCI-MASS (m/z): 571 (M+H)⁺

EXAMPLE 62

A mixture of(2R)-1-(3-methylsulfonylamino-4-benzyloxy)phenyl-2,3-epoxypropane (39mg),(RS)-N-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(58 mg), ytterbium triflate (113 mg) and dichloromethane (1 ml) wasstirred at room temperature overnight. The reaction mixture was washedup in the usual manner. The crude product was dissolved inisopropylalchol (1.5 ml), heated with refluxing for 4.5 hours,evaporated and purified by column chromatography (silica gel, 20 cm³,eluent; 20% ethyl acetate-toluene) to give(2R)-N-[3-(3-methylsulfonylamino-4-benzyloxy)phenyl-2-hydroxypropyl]-N-[(6RS)-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)]benzylamine(40.2 mg) as an oil.

IR (Film): 3272, 2927, 1610, 1508, 1456, 1332, 1261, 1161, 1122, 975cm⁻¹

NMR (CDCl₃, δ): 1.4-1.8 (4H, m), 2.4-3.1 (11H, m), 2.88 (3H, d, J=2.4Hz), 3.5-3.8 (1H, m), 3.79 (3H, s), 5.08 (2H, s), 6.6-6.8 (2H, m),6.9-7.0 (3H, m), 7.1-7.5 (11H, m)

EXAMPLE 63

Under nitrogen, to a solution ofN-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(120 mg) and (2S)-1-(4-acetylamino)phenoxy-2,3-epoxypropane (89 mg) indichloromethane (10 ml) was added ytterbium(III)trifluoromethanesulfonate (50 mg) at room temperature, and the mixturewas stirred at the same temperature for 3 hours. The resulting mixturewas poured into saturated aqueous sodium bicarbonate solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate and evaporated in vacuo. The residue waschromatographed (hexane-ethyl acetate) over silica gel to afford(2S)-1-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-(4-acetylaminophenoxy)-2-propanol(80 mg).

(+) APCI-MASS (m/z): 489 (M+H)⁺

EXAMPLE 64

Under nitrogen, to a solution of2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-N-butylacetamide(200 mg) and (2S)-1-(1H-indol-5-yloxy)-2,3-epoxypropane (130 mg) indichloromethane (10 ml) was added ytterbium(III)trifluoromethanesulfonate (33 mg) at room temperature, and the mixturewas stirred at the same temperature for 3 hours. The resulting mixturewas poured into saturated aqueous sodium bicarbonate solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate and evaporated in vacuo. The residue waschromatographed (hexane-ethyl acetate) over silica gel to afford2-[8-[N-benzyl-N-[(2S)-2-hydroxy-3-(1H-indol-5-yloxy)propyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-butylacetamide(160 mg)

(+) APCI-MASS (m/z): 570 (M+H)⁺

EXAMPLE 65

Under nitrogen, to a solution of2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-N-butylacetamide(388 mg) and (2S)-1-(4-benzyloxyphenoxy)-2,3-epoxypropane (340 mg) indichloromethane (10 ml) was added ytterbium(III)trifluoromethanesulfonate (63 mg) at room temperature, and the mixturewas stirred at the same temperature for 3 hours. The resulting mixturewas poured into saturated aqueous sodium bicarbonate solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate and evaporated in vacuo. The residue waschromatographed (hexane-ethyl acetate) over silica gel to afford2-[8-[N-benzyl-N-[(2S)-3-(4-benzyloxyphenoxy)-2-hydroxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-butylacetamide(300 mg).

(+) APCI-MASS (m/z): 637 (M+H)⁺

EXAMPLE 66

Under nitrogen, to a solution ofN-benzyl-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)aminehydrochloride (300 mg) and (2S)-1-phenoxy-2,3-epoxypropane (193 mg) indichloromethane (10 ml) was added ytterbium(III)trifluoromethanesulfonate (61 mg) at room temperature, and the mixturewas stirred at the same temperature for 3 hours. The resulting mixturewas poured into saturated aqueous sodium bicarbonate solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate and evaporated in vacuo. The residue waschromatographed (hexane-ethyl acetate) over silica gel to afford(2S)-1-[N-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol(340 mg).

NMR (CDCl₃, δ): 1.20-140 (1H, m), 1.60-2.30 (4H, m), 2.50-2.95 (7H, m),3.80-4.05 (5H, m), 6.50-6.75 (2H, m), 6.85-7.03 (4H, m), 7.20-7.38 (8H,m)

(+) APCI-MASS (m/z): 418 (M+H)⁺

EXAMPLE 67

Under nitrogen, to a solution ofN-benzyl-(2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (440 mg) and (2S)-1-phenoxy-2,3-epoxypropane (190 mg) indichloromethane (10 ml) was added ytterbium(III)trifluoromethanesulfonate (157 mg) at room temperature, and the mixturewas stirred at the same temperature for 3 hours. The resulting mixturewas poured into saturated aqueous sodium bicarbonate solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate and evaporated in vacuo. The residue waschromatographed (hexane-ethyl acetate) over silica gel to afford(2S)-1-[N-benzyl-N-(2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol(400 mg).

(+) APCI-MASS (m/z): 462 (M+H)⁺

EXAMPLE 68

Under nitrogen, to a solution ofN-benzyl-(1,4-dimethoxy-5,6,8,9-tetrahdydro-5H-benzocyclohepten-7-yl)amine (200 mg) and (2S)-1-phenoxy-2,3-epoxypropane (100 mg) indichloromethane (10 ml) was added ytterbium(III)trifluoromethanesulfonate (80 mg) at room temperature, and the mixturewas stirred at the same temperature for 3 hours. The resulting mixturewas poured into saturated aqueous sodium bicarbonate solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate and evaporated in vacuo. The residue waschromatographed (hexane-ethyl acetate) over silica gel to afford(2S)-1-[N-benzyl-N-(1,4-dimethoxy-5,6,8,9-tetrahydro-5H-benzocyclohepten-7-yl)amino]-3-phenoxy-2-propanol(70 mg).

(+) APCI-MASS (m/z): 462 (M+H)⁺

EXAMPLE 69

Under nitrogen, to a solution ofN-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)amine(187 mg) and (2S)-1-phenoxy-2,3-epoxypropane (100 mg) in dichloromethane(10 ml) was added ytterbium(III) trifluoromethanesulfonate (50 mg) atroom temperature, and the mixture was stirred at the same temperaturefor 3 hours. The resulting mixture was poured into saturated aqueoussodium bicarbonate solution and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over magnesium sulfate andevaporated in vacuo. The residue was chromatographed (hexane-ethylacetate) over silica gel to afford(2S)-1-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)amino]-3-phenoxy-2-propanol(190 mg).

(+) APCI-MASS (m/z): 432 (M+H)⁺

EXAMPLE 70

To a solution of1-[N-(3-aminomethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)benzylamino]-3-phenoxy-2-propanol(150 mg) in N,N-dimethylformamide (2 ml) and 1N hydrochloric acid (0.8ml) was added potassium cyanate (56.8 mg) at room temperature, and themixture was stirred at the same temperature for 24 hours. The resultingmixture was poured into saturated aqueous sodium bicarbonate solutionand extracted with ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate and evaporated in vacuo. The residuewas chromatographed (hexane-ethyl acetate) over silica gel to affordN-[8-[N′-benzyl-N′-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethyl]urea(160 mg).

(+) APCI-MASS (m/z): 474 (M+H)⁺

EXAMPLE 71

To a solution of1-[N-(3-aminomethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)benzylamino]-3-phenoxy-2-propanol (140 mg) and triethylamine (0.046 ml)in tetrahydrofuran (10 ml) were added chloroformic acid 4-nitrophenylester (66.5 mg) and butylamine (0.030 ml) at room temperature, and themixture was stirred at the same temperature for 18 hours. The resultingmixture was poured into saturated aqueous sodium bicarbonate solutionand extracted with ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate and evaporated in vacuo. The residuewas chromatographed (hexane-ethyl acetate) over silica gel to afford1-[8-N-[benzyl-[(2S)-2-hydroxy-3-phenoxypropyl)amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethyl]-3-butylurea(110 mg).

(+) APCI-MASS (m/z): 530 (M+H)⁺

EXAMPLE 72

To a solution of(2S)-1-[N-(3-aminomethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)benzylamino]-3-phenoxy-2-propanol(100 mg) in methanol (2 ml) was added tert-butylacrylate (0.033 ml) atroom temperature, and the mixture was stirred at the same temperaturefor 18 hours. The resulting mixture was evaporated in vacuo. The residuewas chromatographed (hexane-ethyl acetate) over silica gel to afford3-(8-[N-benzyl-(2S)-(2-hydroxy-3-phenoxypropyl)amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethylamino]-propionicacid tert-butyl ester (100 mg).

(+) APCI-MASS (m/z): 559 (M+H)⁺

EXAMPLE 73

Under nitrogen, to a solution of2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-N-butylacetamide(170 mg) and(2S)-1-(4-benzyloxy-3-methanesulfonylamino)phenoxy-2,3-epoxypropane (108mg) in dichloromethane (10 ml) was added ytterbium(III)trifluoromethanesulfonate (56 mg) at room temperature, and the mixturewas stirred at the same temperature for 3 hours. The resulting mixturewas poured into saturated aqueous sodium bicarbonate solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate and evaporated in vacuo. The residue waschromatographed (hexane-ethyl acetate) over silica gel to afford2-[8-[N-benzyl-N-[(2S)-3-(4-benzyloxy-3-methanesulfonylamino)phenoxy-2-hydroxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-butylacetamide(120 mg).

NMR (CDCl₃, δ): 0.92 (3H, t, J=7.3 Hz), 1.20-1.65 (7H, m), 1.95-2.05(1H, m), 2.60-2.80 (4H, m), 2.60-2.80 (4H, m), 2.87 (3H, s), 3.30-3.40(2H, m), 3.70-4.00 (5H, m), 4.45 (2H, d, J=2.0 Hz), 5.05 (2H, s),6.55-6.75 (2H, m), 6.80-7.25 (14H, m)

(+) APCI-MASS (m/z): 730 (M+H)⁺

EXAMPLE 74

Under nitrogen, to a solution ofN-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(487 mg) and(2S)-1-(4-benzyloxy-3-methanesulfonylamino)phenoxy-2,3-epoxypropane (338mg) in dichloromethane (10 ml) was added ytterbium(III)trifluoromethanesulfonate (107 mg) at room temperature, and the mixturewas stirred at the same temperature for 3 hours. The resulting mixturewas poured into saturated aquous sodium bicarbonate solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate and evaporated in vacuo. The residue waschromatographed (hexane-ethyl acetate) over silica gel to afford(2S)-1-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-(4-benzyloxy-3-methanesulfonylamino)phenoxy-2-propanol(750 mg).

(+) APCI-MASS (m/z): 432 (M+H)⁺

EXAMPLE 75

A mixture of(2S)-1-[N-benzyl-N-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (300 mg) and 10% Pd/C (50% wet, 80 mg) inmethanol (4.5 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 2 hours and 30 minutes andfiltered. The filtrate was evaporated in vacuo, and the residue waschromatographed (chloroform-methanol) over silica gel (6.0 g). Theeluate was treated with 4N hydrogen chloride in ethyl acetate andevaporated in vacuo. The residue was triturated in diethyl ether, andthe precipitated powder was collected by decantation to afford(2S)-1-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanol hydrochloride (238 mg) as a colorless powder.

mp: 53.5° C. (dec.)

IR (KBr): 3411, 2750-2650, 1241 cm⁻¹

NMR (DMSO-d₆, δ): 1.32 (1H, m), 1.75-2.05 (2H, m), 2.24 (1H, m), 2.62(2H, m), 2.95-3.45 (5H, m), 4.00 (2H, m), 4.24 (1H, m), 5.90 (1H, d,J=4.5 Hz), 6.50-6.55 (2H, m), 6.95-7.00 (4H, m), 7.31 (2H, t, J=7.8 Hz),8.77 (1H, br), 9.0 (1H, br), 9.28 (1H, s)

(+) APCI-MASS (m/z): 328 (M+H)⁺ Anal. Calcd. for C₂₀H₂₆ClNO₃.0.5H₂O: C,64.42; H, 7.30; N, 3.76. Found: C, 63.73; H, 7.37; N, 3.58.

EXAMPLE 76

The following compounds [Examples 76 and 77] were obtained according toa similar manner to that of Example 75.

(2S)-1-Phenoxy-3-(6,7,8,9-tetrahydro-1-hydroxy-5H-benzocyclohepten-6-yl)amino-2-propanolhydrochloride

mp: 73-84° C. (dec.) (from diethyl ether)

IR (KBr): 3357 (br), 2850-2650, 1242 cm⁻¹

NMR (DMSO-d₆, δ) 1.23 (2H, m), 1.75-2.05 (2H, m), 2.28 (2H, m),2.95-3.45 (5H, m), 4.00 (2H, m), 4.22 (1H, m), 5.90 (1H, J=4.9 Hz),6.63-6.75 (2H, m), 6.87-7.00 (4H, m), 7.27-7.36 (2H, m), 8.74 (1H, br),8.95 (1H, br), 9.34 (1H, s)

(+) APCI-MASS (m/z): 328 (M+H)⁺ Anal. Calcd. for C₂₀H₂₆ClNO₃.1/4H₂O: C,65.21; H, 7.25; N, 3.80. Found: C, 65.24; H, 7.50; N, 3.61.

EXAMPLE 77

1-(1,3-Dihydro-2-benzoimidazolon-4-yl)oxy-3-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amino-2-propanolhydrochloride

mp 100.5° C. (dec.) (from diisopropyl ether)

IR (KBr): 3410 (br), 3257 (br), 2800-2650, 1695, 1259, 1244 cm⁻¹

NMR (DMSO-d₆, δ): 1.12-1.4 (1H, m), 1.75-2.2 (2H, m), 2.2-2.4 (1H, m),2.4-2.8 (2H, m), 2.8-3.5 (5H, m), 3.95-4.3 (3H, m), 5.7 (1H, br),6.51-6.66 (4H, m), 6.88 (1H, t, J=8.2 Hz), 6.99 (1H, d, J=6.9 Hz), 8.68(1H, br), 8.93 (1H, br), 9.25 (1H, br)

(+) APCI-MASS (m/z): 384 (M+H)⁺

EXAMPLE 78

A mixture of(2S)-1-[N-benzyl-N-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanolhydrochloride (121 mg) and 10% Pd/C (50% wet, 18 mg) in chlorobenzene(1.8 ml) and MeOH (0.4 ml) was stirred at room temperature in thepresence of hydrogen at an atmospheric pressure for 1 hour and filtered.The filtrate was evaporated in vacuo, and the residue was partitionedbetween ethyl acetate and a saturated aqueous solution of sodiumbicarbonate. The organic layer was separated, washed with brine, driedover sodium sulfate and evaporated in vacuo. The residue waschromatographed (dichloromethane-methanol) over silica gel (2.0 g). Theeluate was treated with 4N hydrogen chloride in ethyl acetate andevaporated in vacuo. The residue was triturated in diisopropyl ether,and the precipitated powder was collected by filtration to afford(2S)-1-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5-H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride (74 mg, 75%) as a colorless powder.

IR (KBr): 3384 (br), 2800-2600, 1242 cm⁻¹

NMR (DMSO-d₆, δ): 1.17-1.31 (1H, m), 1.84-1.99 (2H, m), 2.16-2.24 (1H,m), 2.61-2.74 (2H, m), 3.00-3.22 (4H, m), 3.98-4.24 (3H, m), 5.89 (1H,d, J=3.9 Hz), 6.77 (1H, m), 6.86-7.02 (3H, m), 7.14-7.32 (3H, m), 8.73(1H, br), 8.88 (1H, br), 10.03 (1H, s)

(+) APCI-MASS (m/z): 362 and 364 (M+H)⁺

EXAMPLE 79

A mixture of(2S)-1-[N-benzyl-N-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol(281 mg) and 10% palladium on activated carbon (50% wet, 100 mg) inmethanol (5 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 6 hours. After filtration, thefiltrate was evaporated in vacuo, followed by treatment with 4N hydrogenchloride in ethyl acetate to give(2S)-1-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride (130 mg).

(+) APCI-MASS (m/z): 370 (M−HCl+H)⁺

The following compounds [Examples 80 to 108] were obtained according toa similar manner to that of Example 79.

EXAMPLE 80

(2S)-1-(3-Hexyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride

NMR (DMSO-d₆, δ): 0.8 (3H, m), 1.1-1.5 (7H, m), 1.6-2.15 (4H, m),2.25-2.4 (1H, m), 2.5-2.8 (2H, m), 2.9-3.5 (5H, m), 3.85-4.1 (4H, m),4.15-4.25 (1H, m), 5.9-6.05 (1H, m), 6.65-7.1 (6H, m), 7.2-7.4 (2H, m),8.7-9.3 (2H, m)

(+) APCI-MASS (m/z): 412 (M+H)⁺

EXAMPLE 81

(2S)-1-[3-(3-Cyano-pyridin-2-yl)oxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanolhydrochloride

(+) ESI-MASS (m/z): 464 (M−HCl−H)⁺

EXAMPLE 82

(2S)-1-[3-(2-Methoxyethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]amino-3-phenoxy-2-propanolhydrochloride

(+) APCI-MASS (m/z): 386 (M−HCl+H)⁺

EXAMPLE 83

N-(2-Dimethylaminoethyl)-2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamidedihydrochloride

(+) APCI-MASS (m/z): 456 (M−HCl+H)⁺

EXAMPLE 84

(2S)-1-(3-Amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanoldihydrochloride

(+) APCI-MASS (m/z): 327 (M−HCl+H)⁺

EXAMPLE 85

(2S)-1-(3-Dimethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride

(+) APCI-MASS (m/z): 355 (M−HCl+H)⁺

EXAMPLE 86

(2S)-1-(3-Dimethylamino-6,7,8,9-terahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride

(+) APCI-MASS (m/z): 355 (M−HCl+H)⁺

EXAMPLE 87

N-[8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]acetamidehydrochloride

(+) ESI-MASS (m/z): 369 (M−HCl+H)⁺

EXAMPLE 88

N-[8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]benzamidehydrochloride

(+) APCI-MASS (m/z): 431 (M−HCl+H)⁺

EXAMPLE 89

N-[8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]methanesulfonamidehydrochloride

(+) APCI-MASS (m/z): 405 (M−HCl+H)⁺

EXAMPLE 90

N-[8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]benzenesulfonamidehydrochloride

(+) APCI-MASS (m/z): 467 (M−HCl+H)⁺

EXAMPLE 91

6-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-3-methoxycarbonylamino-6,7,8,9-tetrahydro-5H-benzocycloheptenehydrochloride

(+) APCI-MASS (m/z): 385 (M−HCl+H)⁺

EXAMPLE 92

6-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-3-phenoxycarbonylamino-6,7,8,9-tetrahydro-5H-benzocycloheptenehydrochloride

(+) APCI-MASS (m/z): 447 (M−HCl+H)⁺

EXAMPLE 93

N,N-Dimethyl-N′-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]sulfonamidehydrochloride

(+) APCI-MASS (m/z): 434 (M−HCl+H)⁺

EXAMPLE 94

N-[8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]sulfonamidehydrochloride

(+) APCI-MASS (m/z): 406 (M−HCl+H)⁺

EXAMPLE 95

(2S)-3-Phenoxy-1-(6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-2-propanolhydrochloride

(+) ESI-MASS (m/z): 312 (M−HCl+H)⁺

EXAMPLE 96

(2S)-1-Phenoxy-3-(3-phenyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-2-propanolhydrochloride

(+) ESI-MASS (m/z): 388 (M−HCl+H)⁺

EXAMPLE 97

(2S)-3-Phenylsulfonyl-1-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-2-propanolhydrochloride

(+) APCI-MASS (m/z): 390 (M−HCl+H)⁺

EXAMPLE 98

1-(3-Methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenylamino-2-propanoldihydrochloride

(+) APCI-MASS (m/z): 341 (M−2HCl+H)⁺

EXAMPLE 99

(2S)-1-(6-Aminopyridin-3-yl)oxy-3-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-2-propanolhydrochloride

(+) APCI-MASS (m/z): 358 (M−3HCl+H)⁺

EXAMPLE 100

(2S)-1-(4-Fluorophenoxy)-3-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-2-propanolhydrochloride

NMR (DMSO-d₆, δ) 1.1-1.4 (1H, m), 1.7-2.1 (2H, m), 2.2-2.4 (1H, m),2.6-2.8 (2H, m), 2.95-3.5 (5H, m), 3.72 (3H, s), 3.9-4.0 (2H, m) , 4.22(1H, br s), 5.93 (1H, br s), 6.71 (1H, dd, J=2.6 and 8.2 Hz), 6.82 (1H,dd, J=2.6 and 6.5 Hz) , 6.9-7.25 (5H, m), 8.82 (1H, br s), 9.16 (1H, brs)

(+) APCI-MASS (m/z): 360 (M−HCl+H)⁺

EXAMPLE 101

(2S)-1-(4-Methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride

IR (KBr): 3369, 2937, 1591, 1452, 1259, 1236, 1074 cm⁻¹

NMR (DMSO-d₆, δ): 1.22-1.42 (1H, m), 1.80-2.10 (2H, m), 2.25-2.39 (1H,m), 2.66-2.83 (3H, m), 2.90-3.23 (3H, m), 3.53-3.60 (1H, m), 3.78 (3H,s), 3.98-4.05 (2H, m), 4.20-4.31 (1H, m), 5.91 (1H, br), 6.75 (1H, d,J=7.9 Hz), 6.86 (1H, d, J=7.9 Hz), 6.92-7.00 (3H, m), 7.12 (1H, dd,J=7.9 and 7.9 Hz), 7.32 (2H, dd, J=8.1 and 8.1 Hz), 8.89 (2H, br)

(+) APCI-MASS (m/z): 342 (M+H)⁺

EXAMPLE 102

8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylicacid methyl ester hydrochloride

IR (KBr): 3378, 2950, 2796, 1716, 1438, 1280, 1243 cm⁻¹

NMR (DMSO-d₆, δ) 1.20-1.42 (1H, m), 1.81-2.13 (2H, m), 2.25-2.40 (1H,m), 2.74-2.91 (2H, m), 3.02-3.37 (5H, m), 3.84 (3H, s), 4.01 (2H, d,J=4.6 Hz), 4.20-4.36 (1H, m), 5.93 (1H, br), 6.92-6.99 (3H, m),7.27-7.35 (3H, m), 7.76 (1H, d, J=7.8 Hz), 7.87 (1H, d, J=7.8 Hz),8.92-9.18 (2H, br)

(+) ESI-MASS (m/z): 370 (M+H)⁺

EXAMPLE 103

8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxamidehydrochloride

IR (KBr): 3353, 2937, 1662, 1600, 1243 cm⁻¹

NMR (DMSO-d₆, δ): 1.21-1.42 (1H, m), 1.78-2.13 (2H, m), 2.24-2.40 (1H,m), 2.74-2.85 (2H, m), 3.02-3.44 (5H, m), 4.01 (2H, d, J=4.5 Hz),4.18-4.30 (1H, m), 5.92 (1H, d, J=4.0 Hz), 6.92-6.99 (3H, m), 7.21 (1H,d, J=7.8 Hz) , 7.27-7.35 (3H, m), 7.67 (1H, d, J=7.8 Hz), 7.79 (1H, d,J=2.0 Hz), 7.91 (1H, s), 8.84 (1H, br s), 9.12 (1H, br s)

(+) APCI-MASS (m/z): 355 (M+H)⁺

EXAMPLE 104

N-[8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethyl]acetamidehydrochloride

IR (KBr) 3278, 2935, 1648, 1494, 1241 cm⁻¹

NMR (DMSO-d₆, δ): 1.17-1.37 (1H, m), 1.78-2.10 (2H, m), 1.86 (3H, s),2.25-2.37 (1H, m), 2.67-2.77 (2H, m), 2.98-3.40 (5H, m), 4.01 (2H, d,J=3.9 Hz), 4.15-4.35 (1H, m), 4.19 (2H, d, J=5.7 Hz), 6.92-7.10 (6H, m),7.31 (2H, dd, J=7.8 and 7.8 Hz), 8.30-8.40 (1H, m), 8.85 (1H, br s),9.20 (1H, br s)

(+) APCI-MASS (m/z): 383 (M+H)⁺

EXAMPLE 105

N-[8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethyl]benzamidehydrochloride

IR (KBr): 3330, 2933, 1639, 1538, 1455, 1241 cm⁻¹

NMR (DMSO-d₆, δ) 1.18-1.38 (1H, m), 1.79-2.08 (2H, m), 2.23-2.37 (1H,m), 2.68-2.78 (2H, m), 2.98-3.30 (5H, m), 3.97-4.03 (2H, m), 4.16-4.28(1H, m), 4.44 (2H, d, J=5.4 Hz), 5.91 (1H, br), 6.91-6.98 (3H, m),7.10-7.18 (3H, m), 7.30 (2H, dd, J=7.7 and 7.7 Hz), 7.41-7.57 (3H, m),7.91 (2H, d, J=7.7 Hz), 8.75-9.10 (2H, br), 9.03-9.13 (1H, m)

(+) APCI-MASS (m/z): 445 (M+H)⁺

EXAMPLE 106

N-[8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethyl]methanesulfonamidehydrochloride

IR (KBr): 3326, 2933, 1594, 1496, 1313, 1241, 1147 cm⁻¹

NMR (DMSO-d₆, δ): 1.15-1.38 (1H, m), 1.75-2.09 (2H, m), 2.23-2.37 (1H,m), 2.68-2.78 (2H, m), 2.87 (3H, s), 2.93-3.32 (5H, m), 4.00 (2H, d,J=4.1 Hz), 4.10 (2H, d, J=6.3 Hz), 4.17-4.30 (1H, m), 5.93 (1H, br),6.91-7.00 (3H, m), 7.11-7.20 (3H, m), 7.31 (2H, dd, J=7.8 and 7.8 Hz),7.50-7.59 (1H, m), 8.80-9.10 (2H, br)

(+) APCI-MASS (m/z): 419 (M+H)⁺

EXAMPLE 107

N-[8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethyl]benzenesulfonamidehydrochloride

IR (KBr): 2935, 1594, 1496, 1448, 1322, 1241, 1157 cm⁻¹

NMR (DMSO-d₆, δ): 1.13-1.38 (1H, m), 1.75-2.08 (2H, m), 2.24-2.38 (1H,m), 2.65-2.75 (2H, m), 2.92-3.35 (5H, m), 3.92 (2H, d, J=6.2 Hz), 4.01(2H, d, J=4.4 Hz), 4.18-4.30 (1H, m), 5.92 (1H, br), 6.92-7.02 (5H, m),7.10 (1H, s), 7.31 (2H, dd, J=7.8 and 7.8 Hz), 7.50-7.68 (3H, m), 7.79(2H, d, J=7.8 Hz), 8.12-8.22 (1H, m), 8.86 (2H, br)

(+) APCI-MASS (m/z): 481 (M+H)⁺

EXAMPLE 108

1-(3-Methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-4-phenyl-2-butanolhydrochloride

(+) APCI-MASS (m/z): 340 (M−HCl+H)⁺

EXAMPLE 109

A solution ofN-(3-ethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine(115 mg) and concentrated hydrochloric acid (0.5 ml) in methanol (5 ml)was stirred at room temperature for 48 hours. The mixture was evaporatedin vacuo. The residue was triturated with diethyl ether-diisopropylether, followed by decantation and dryness in vacuo to give(2S)-1-(3-ethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride (30 mg).

NMR (DMSO-d₆, δ) 1.1-1.4 (4H, m), 1.7-2.1 (2H, m), 2.2-2.35 (1H, m),2.55-2.75 (2H, m), 2.9-3.4 (5H, m), 3.9-4.1 (4H, m), 4.25 (1H, br s),5.9-6.0 (1H, m), 6.69 (1H, dd, J=2.5 and 8.2 Hz), 6.82 (1H, dd, J=2.4and 6.8 Hz), 6.9-7.1 (4H, m), 7.31 (2H, t, J=7.9 Hz), 8.7-9.4 (2H, m)

(+) APCI-MASS (m/z): 356 (M+H)⁺

EXAMPLE 110

ToN-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine(79 mg) was added 4N hydrogen chloride in ethyl acetate (3 ml) at roomtemperature, and the mixture was stirred at room temperature for 1 hour.After evaporation in vacuo, the residue was triturated with diisopropylether and dried in vacuo to give(2S)-1-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride (35 mg)

(+) APCI-MASS (m/z): 370 (M−HCl+H)⁺

The following compounds [Examples 111 to 116] were obtained according toa similar manner to that of Example 110.

EXAMPLE 111

(2S)-1-(3-Allyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride

(−) ESI-MASS (m/z): 402 (M−HCl−H)⁺

EXAMPLE 112

(2S)-1-(3-Cyclopentyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride

(+) APCI-MASS (m/z): 396 (M−HCl+H)⁺

EXAMPLE 113

(2S)-1-(3-Benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride

(+) APCI-MASS (m/z): 418 (M−HCl+H)⁺

EXAMPLE 114

(2S)-1-(3-Phenethyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride

(+) APCI-MASS (m/z): 432 (M−HCl+H)⁺

EXAMPLE 115

(2S)-1-(3-Carbamoyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride

(+) APCI-MASS (m/z) 371 (M−HCl+H)⁺

EXAMPLE 116

(2S)-1-(3-Dimethylsulfonyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanol

NMR (DMSO-d₆, δ) 1.2-1.45 (1H, m), 1.7-2.1 (2H, m), 2.3-2.4 (1H, m),2.7-3.35 (7H, m), 2.90 (6H, m), 4.00 (2H, d, J=8.6 Hz), 4.2-4.35 (1H,m), 6.9-7.35 (8H, m)

(+) APCI-MASS (m/z): 435 (M−HCl+H)⁺

EXAMPLE 117

To a solution ofN-(3-fluoromethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-2-hydroxy-3-phenoxypropyl]-tert-butoxycarbonylamine(41 mg) in ethyl acetate (2 ml) was added 4N hydrogen chloride in ethylacetate (0.45 ml) at room temperature, and the mixture was stirred atthe same temperature for 5.5 hours. The mixture was poured into amixture of saturated aqueous sodium hydrogencarbonate and ethyl acetate,followed by being made basic with saturated aqueous sodiumhydrogencarbonate. After separation, the organic layer was dried overanhydrous magnesium sulfate and evaporated in vacuo. The residue waspurified by preparative thin layer chromatography (silica gel,chloroform:methanol=10:1) to give(2S)-1-(3-fluoromethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanol(23 mg).

(+) APCI-MASS (m/z): 360 (M+H)⁺

EXAMPLE 118

A mixture of2-[8-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamidemethanesulfonate (240 mg) and 10% palladium on activated carbon (50%wet, 50 mg) in ethanol (5 ml) was stirred at room temperature in thepresence of hydrogen at an atmospheric pressure for 2 hours. Afterfiltration, the filtrate was evaporated in vacuo and followed bytrituration with diisopropyl ether to give2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamidemethanesulfonate (187 mg).

(+) APCI-MASS (m/z): 385 (M−MsOH+H)⁺

EXAMPLE 119

A solution of2-[8-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid ethyl ester (200 mg) and ethylamine (70% in water, 77 μl) inmethanol (2 ml) were stirred at room temperature for 12 hours. Afterevaporation in vacuo, the crude product and 10% palladium on activatedcarbon (50% wet, 60 mg) in methanol (2 ml) were stirred at roomtemperature in the presence of hydrogen at an atmospheric pressure for2.5 hours. After filtration, the filtrate was evaporated in vacuo. Theresidue was purified by column chromatography on silica gel(chloroform:methanol=10:1) and followed by treatment with 4N hydrogenchloride in ethyl acetate to giveN-ethyl-2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamidehydrochloride (120 mg).

NMR (DMSO-d₆, δ): 1.0-1.1 (3H, m), 1.1-1.4 (1H, m), 1.7-2.1 (2H, m),2.25-2.4 (1H, m), 2.6-2.8 (2H, m), 2.9-3.7 (7H, m), 3.95-4.1 (2H, m),4.15-4.35 (1H, m), 4.40 (2H, s), 6.73 (1H, dd, J=2.6 and 8.3 Hz),6.85-7.1 (5H, m), 7.31 (2H, t, J=8.0 Hz), 8.15-8.2 (1H, m), 8.7-9.3 (2H,m)

EXAMPLE 120

A solution of2-[8-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid ethyl ester (220 mg) and n-hexylamine (173 μl) in methanol (2 ml)was stirred at room temperature for 36 hours. And then to this one wasadded 10% palladium on activated carbon (50% wet, 60 mg), and themixture was stirred at room temperature in the presence of hydrogen atan atmospheric pressure for 4 hours. After filtration, the filtrate wasevaporated in vacuo. The residue was purified by preparative thin layerchromatography (silica gel, chloroform:methanol=10:1) and followed bytreatment with 4N hydrogen chloride in ethyl acetate to giveN-hexyl-2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamidehydrochloride (169 mg).

(+) APCI-MASS (m/z): 469 (M−HCl+H)⁺

The following compound was obtained according to a similar manner tothat of Example 120.

EXAMPLE 121

2-[8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-(2-methoxyethyl)acetamidehydrochloride

NMR (DMSO-d₆, δ): 1.1-1.4 (1H, m), 1.7-2.1 (2H, m), 2.25-2.4 (1H, m),2.6-2.8 (2H, m), 3.0-3.45 (12H, m) , 3.95-4.1 (2H, m) , 4.2-4.35 (1H, m), 4.43 (2H, s), 5.9-6.0 (1H, m), 6.7-6.8 (1H, m), 6.85-7.1 (5H, m),7.25-7.4 (2H, m), 8.0-8.1 (1H, m), 8.7-9.3 (2H, m)

(+) APCI-MASS (m/z): 443 (M−HCl+H)⁺

EXAMPLE 122

To a solution ofN-[3-(N′-butylmethylcarbamoyl)methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]-tert-butoxycarbonylamine(85 mg) in ethyl acetate (2 ml) was added 4N hydrogen chloride in ethylacetate (1 ml) at 5° C., and the mixture was stirred at room temperaturefor 2 hours. After evaporation in vacuo, the residue was triturated withdiisopropyl ether and dried in vacuo to giveN-butyl-2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-methylacetamidehydrochloride (45 mg).

NMR (DMSO-d₆, δ): 0.88 (3H, q, J=7.3 Hz), 1.10-1.65 (5H, m), 1.70-2.16(2H, m), 2.23-2.40 (1H, m), 2.58-3.43 (12H, m), 3.85-4.10 (2H, m),4.17-4.35 (1H, m), 4.73 (2H, s), 5.83-5.99 (1H, m), 6.59-7.08 (6H, m),7.31 (2H, t, J=7.7 Hz), 8.81 (1H, br s), 9.15 (1H, br s)

(+) APCI-MASS (m/z): 455 (M+H)⁺

The following compounds [Examples 123 to 128] were obtained according toa similar manner to that of Example 122.

EXAMPLE 123

N-sec-Butyl-2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamidehydrochloride

(+) APCI-MASS (m/z): 441 (M+H)⁺

EXAMPLE 124

N-Cyclohexyl-2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamidehydrochloride

(+) APCI-MASS (m/z): 467 (M+H)⁺

EXAMPLE 125

N-Benzyl-2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamidehydrochloride

(+) APCI-MASS (m/z): 475 (M+H)⁺

EXAMPLE 126

2-[8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-(2-methylthioethyl)acetamidehydrochloride

(+) APCI-MASS (m/z): 459 (M+H)⁺

EXAMPLE 127

6-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-3-piperidinocarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptenehydrochloride

(+) APCI-MASS (m/z): 453 (M+H)⁺

EXAMPLE 128

2-[8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-(1H-indol-5-yl)acetamidehydrochloride

NMR (DMSO-d₆, δ): 1.14-1.49 (1H, m), 1.70-2.12 (2H, m),

2.25-2.39 (1H, m), 2.57-2.82 (2H, m), 2.94-4.13 (7H, m), 4.19-4.32 (1H,m), 4.52-4.78 (2H, m), 6.72-7.49 (13H, m), 7.50-7.93 (1H, m), 8.69-9.33

(+) APCI-MASS (m/z): 500 (M+H)⁺

EXAMPLE 129

Under nitrogen, to a solution of (2S)-1-amino-3-phenoxy-2-propanol (280mg) in 1,2-dichloroethane (10 ml) were added3-chloro-5,7,8,9-tetrahydrobenzocyclohepten-6-one (300 mg), sodiumtriacetoxyborohydride (820 mg) and acetic acid (0.26 ml) at roomtemperature, and the mixture was stirred at the same temperature for 6.5hours. The resulting mixture was poured into aqueous 1N sodium hydroxideand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and evaporated in vacuo.The residue was purified by column chromatography on silica gel(chloroform:methanol=20:1 to 10:1) and followed by treatment with 4Nhydrogen chloride in ethyl acetate to give(2S)-1-(3-chloro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride (260 mg).

(+) ESI-MASS (m/z): 346, 348 (M−HCl+H)⁺

The following compounds [Examples 130 and 131] were obtained accordingto a similar manner to that of Example 129.

EXAMPLE 130

(2S)-1-(3-Nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride

(+) ESI-MASS (m/z): 357 (M−HCl+H)⁺

EXAMPLE 131

(2S)-1-(3-Methyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride

(+) ESI-MASS (m/z): 325 (M−HCl+H)⁺

EXAMPLE 132

A mixture of(2S)-1-[N-benzyl-N-(2-chloro-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (172 mg) and 10% palladium on activatedcarbon (50% wet, 50 mg) in a mixture of chlorobenzene (2 ml) andmethanol (2 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 2 hours. After filtration, thefiltrate was evaporated in vacuo. The residue was purified by columnchromatography on silica gel (chloroform:methanol=20:1 to 10:1) andfollowed by treatment with 4N hydrogen chloride in ethyl acetate to give1-(2-chloro-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride (95 mg).

(+) APCI-MASS (m/z): 376, 378 (M−HCl+H)⁺

EXAMPLE 133

Under nitrogen, to a solution of3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamine (330 mg) and(2S)-1-phenylthio-2,3-epoxypropane (290 mg) in dichloromethane (5 ml)was added ytterbium(III) trifluoromethanesulfonate (110 mg) at roomtemperature, and the mixture was stirred at the same temperature for 24hours. The resulting mixture was poured into saturated aqueous sodiumhydrogencarbonate and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel (chloroform:methanol=50:1 to 20:1) followed by treatmentwith 4N hydrogen chloride in ethyl acetate to give(2S)-1-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenylthio-2-propanol hydrochloride (360 mg).

(+) APCI-MASS (m/z): 358 (M−HCl+H)⁺

EXAMPLE 134

8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylicacid methyl ester hydrochloride was converted to the corresponding freebase in a usual manner. A solution of the base (91 mg) in methanol (1ml) and 1N sodium hydroxide aqueous solution (0.246 ml) was stirred at70° C. for 6 hours and evaporated in vacuo. The residue was trituratedin diisopropyl ether, and the precipitated powder was collected byfiltration to afford sodium8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylate(74 mg).

IR (KBr): 3380, 2925, 1592, 1550,1386, 1245 cm⁻¹

NMR (DMSO-d₆, δ) 1.23-1.70 (3H, m), 1.75-2.06 (2H, m), 2.38-2.90 (7H,m), 3.79-3.98 (3H, m), 5.11 (1H, br), 6.87-6.98 (4H, m), 7.27 (2H, dd,J=8.0 and 8.0 Hz), 7.58 (1H, d, J=7.5 Hz), 7.65 (1H, s)

(+) ESI-MASS (m/z): 356 (M−Na+2H)⁺, 378 (M+H)⁺

EXAMPLE 135

A solution ofN-[(2S)-2-hydroxy-3-phenoxypropyl]-N-(3-methylcarbamoyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine(108 mg) in ethyl acetate (1 ml) was treated with 4N hydrogen chloridein ethyl acetate solution (0.58 ml) overnight. The mixture wasevaporated in vacuo and triturated in diisopropyl ether, and theprecipitated powder was collected by filtration to afford6-[(2S)-2-hydroxy-3-phenoxypropyl]amino-3-methylcarbamoyl-6,7,8,9-tetrahydro-5H-benzocycloheptenehydrochloride (86 mg).

IR (KBr): 3332, 2937, 1631, 1457, 1241 cm⁻¹

NMR (DMSO-d₆, δ): 1.22-1.42 (1H, m), 1.80-2.11 (2H, m), 2.23-2.39 (1H,m), 2.77 (3H, d, J=4.4 Hz), 2.79-2.86 (2H, m), 3.02-3.45 (5H, m), 4.00(2H, d, J=4.0 Hz), 4.19-4.30 (1H, m), 5.83 (1H, br), 6.92-6.99 (3H, m),7.21 (1H, d, J=7.8 Hz), 7.31 (2H, dd, J=8.0 and 8.0 Hz), 7.62 (1H, d,J=7.3 Hz), 7.75 (1H, s), 8.40 (1H, t like, J=4.4 Hz), 8.81 (1H, br s),9.09 (1H, br s)

(+) ESI-MASS (m/z): 369 (M+H)⁺

The following compounds [Examples 136 and 137] were obtained accordingto a similar mannder to that of Example 135.

EXAMPLE 136

6-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-3-dimethylcarbamoyl-6,7,8,9-tetrahydro-5H-benzocycloheptenehydrochloride

IR (KBr) 3382, 2935, 1602, 1492, 1241 cm⁻¹

NMR (DMSO-d₆, δ) 1.22-1.43 (1H, m), 1.83-2.10 (2H, m), 2.23-2.38 (1H,m), 2.76-2.83 (2H, m), 2.94 (6H, s), 3.00-3.40 (5H, m), 3.97-4.03 (2H,m), 4.18-4.30 (1H, m), 6.90-7.02 (3H, m), 7.19-7.35 (5H, m), 8.80 (1H,br), 9.10 (1H, br)

(+) ESI-MASS (m/z): 383 (M+H)⁺

EXAMPLE 137

6-[(2S)-2-Hydroxy-3-phenylpropyl]amino-3-phenylcarbamoyl-6,7,8,9-tetrahydro-5H-benzocycloheptenehydrochloride

IR (KBr): 3380, 2937, 1648, 1598, 1536, 1498, 1241 cm⁻¹

NMR (DMSO-d₆, δ): 1.20-1.44 (1H, m), 1.80-2.18 (2H, m), 2.20-2.40 (1H,m), 2.78-2.90 (2H, m), 3.02-3.40 (5H, m), 3.98-4.08 (2H, m), 4.18-4.31(1H, m), 5.92 (1H, d, J=4.9 Hz), 6.91-6.99 (4H, m), 7.09 (1H, dd, J=7.3and 7.3 Hz), 7.26-7.39 (5H, m), 7.75-7.87 (4H, m), 8.76 (1H, br), 8.91(1H, br), 10.21 (1H, s)

(+) ESI-MASS (m/z): 431 (M+H)⁺

EXAMPLE 138

ToN-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine(200 mg) was added 4N hydrogen chloride in ethyl acetate (6 ml) at roomtemperature, and the mixture was stirred at the same temperature for 1hour. After evaporation in vacuo, the residue was dissolved into amixture of saturated aqueous sodium hydrogencarbonate and ethyl acetate.After separation, the organic layer was washed with brine, dried overanhydrous magnesium sulfate and evaporated in vacuo. The residue waspurified by preparative thin layer chromatography (silica gel,chloroform:methanol=5:1) and followed by treatment with 4N hydrogenchloride in ethyl acetate to give(2S)-1-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanolhydrochloride (45 mg).

(+) APCI-MASS (m/z): 342 (M−HCl+H)⁺

EXAMPLE 139

A solution ofN-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine(188 mg) in ethyl acetate (2 ml) was treated with 4N hydrogen chloridein ethyl acetate (2 ml) for 3 hours. The mixture was evaporated in vacuoand washed with diethyl ether three times. The residue was triturated indiisopropyl ether, and precipitated powder was collected by filtrationto afford6-[(2S)-2-hydroxy-3phenoxypropyl]amino-3-acetyloxymethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene(113 mg).

NMR (DMSO-d₆, δ): 1.12-1.41 (1H, m), 1.75-2.10 (2H, m), 2.05 (3H, s),2.22-2.39 (1H, m), 2.65-2.85 (2H, m), 2.97-3.37 (5H, m), 3.94-4.04 (2H,m), 4.18-4.35 (1H, m), 5.02 (2H, s), 5.93 (1H, d, J=4.3 Hz), 6.92-7.00(3H, m), 7.08-7.38 (5H, m), 8.89 (1H, br), 9.27 (1H, br)

(+) APCI-MASS (m/z): 384 (M+H)⁺

The following compound was obtained according to a similar manner tothat of Example 139.

EXAMPLE 140

(2S)-1-(3-Dimethylaminomethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanoldichloride

IR (KBr): 3380, 2937, 2709, 1594, 1494, 1457, 1243 cm⁻¹

NMR (DMSO-d₆, δ) 1.12-1.43 (1H, m), 1.80-2.10 (2H, m), 2.22-2.42 (1H,m), 2.67 (6H, s), 2.72-2.88 (2H, m), 2.98-3.45 (5H, m), 3.95-4.05 (2H,m), 4.10-4.35 (3H, m), 5.92 (1H, br), 6.90-7.02 (3H, m), 7.16-7.42 (5H,m), 8.87 (1H, br), 9.27 (1H, br), 10.81 (1H, br)

(+) APCI-MASS (m/z): 369 (M+H)⁺

EXAMPLE 141

A mixture ofN-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]methylacetamide hydrochloride (100 mg) and 1N aqueous hydrochloric acidsolution (2 ml) was heated to reflux for 18 hours. The solvent wasremoved under reduced pressure to dryness. The residue was triturated indiisopropyl ether, and the precipitated powder was collected byfIltration to afford(2S)-1-[(3-aminomethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanoldihydrochloride (94 mg).

IR (KBr) 3382, 2933, 1594, 1494, 1241 cm⁻¹

NMR (DMSO-d₆, δ): 1.12-1.38 (1H, m), 1.77-2.10 (2H, m), 2.28-2.42 (1H,m), 2.70-2.82 (2H, m), 2.95-3.32 (5H, m), 3.88-4.00 (2H, m), 4.02 (2H,d, J=4.6 Hz), 4.23-4.33 (1H, m), 5.94 (1H, br), 6.92-6.99 (3H, m), 7.18(1H, d, J=7.5 Hz), 7.27-7.74 (4H, m), 8.49 (3H, br s), 9.00 (1H, br s),9.46 (1H, br s)

(+) APCI-MASS (m/z): 341 (M+H)⁺

EXAMPLE 142

A mixture ofN-[(2R)-3-(3-methylsulfonylamino-4-benzyloxy)phenyl-2-hydroxypropyl]-N-[(6RS)-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)benzylamine(34 mg), 50% wet palladium (10%) on charcoal (10 mg) and methanol (1 ml)was stirred under hydrogen (1 atm) at room temperature for 1.5 hours.The reaction mixture was filtered and evaporated. The residue waspurified by preparative TLC (eluent; 25% methanol-dichloromethane) togiveN-[(2R)-3-(3-methylsulfonylamino-4-hydroxy)phenyl-2-hydroxypropyl]-[(6RS)-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]amine(6.9 mg).

IR (KBr): 3446, 2925, 1612, 1500, 1267, 1157, 1106 cm⁻¹

NMR (CD₃OD, δ) 1.4-2.2 (4H, m), 2.40-2.9 (9H, m), 2.86 (3H, d, J=2.0Hz), 3.74 (3H, s), 3.7-3.9 (1H, m), 6.57-6.83 (4H, m), 6.95 (1H, d,J=8.1 Hz), 7.15 (1H, br s)

MASS (m/z): 435 (M)⁺

EXAMPLE 143

A mixture of(2S)-3-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-1-(4-acetylamino)phenoxy-2-propanol(80 mg) and 10% palladium on activated carbon (50% wet, 10 mg) inmethanol (10 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 3 hours and filtered. Thefiltrate was evaporated in vacuo and treated with 4N hydrogen chloridein ethyl acetate to afford(2S)-3-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-1-(4-acetylamino)-phenoxy-2-propanolhydrochloride (80 mg).

(+) APCI-MASS (m/z): 435 (M+H)⁺

EXAMPLE 144

A mixture of2-[8-[N′-benzyl-[(2S)-2-hydroxy-3-(1H-indol-5-yloxy)propyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]oxy-N-butylacetamide(160 mg) and 10% palladium on activated carbon (50% wet, 30 mg) inmethanol (10 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 3 hours and filtered. Thefiltrate was evaporated in vacuo and treated with 4N hydrogen chloridein ethyl acetate to affordN-butyl-2-[8-[(2S)-2-hydroxy-3-(1H-indol-5-yloxy)propylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamidehydrochloride (133 mg).

(+) APCI-MASS (m/z): 480 (M+H)⁺

EXAMPLE 145

A mixture of2-[8-[N′-benzyl-N′-[(2S)-3-(4-benzyloxyphenoxy)-2-hydroxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]oxy-N-butylacetamide(300 mg) and 10% palladium on activated carbon (50% wet, 100 mg) inmethanol (10 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 3 hours and filtered. Thefiltrate was evaporated in vacuo and treated with 4N hydrogen chloridein ethyl acetate to affordN-butyl-2-[8-[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamidehydrochloride (190 mg).

(+) APCI-MASS (m/z): 457 (M+H)⁺

EXAMPLE 146

A mixture of(2S)-1-[N-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol(320 mg) and 10% palladium on activated carbon (50% wet, 100 mg) inmethanol (20 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 3 hours and filtered. Thefiltrate was evaporated in vacuo and treated with 4N hydrogen chloridein ethyl acetate to afford(2S)-1-[3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanolhydrochloride (161 mg).

NMR (DMSO-d₆, δ): 1.20-1.35 (1H, m), 1.75-2.10 (2H, m), 2.20-2.30 (1H,m), 2.60-2.75 (2H, m), 2.90-3.35 (5H, m), 4.00 (2H, s), 4.22 (1H, br s),5.90 (1H, d, J=4.8 Hz), 6.50-6.70 (2H, m), 6.80-7.05 (4H, m), 7.20-7.45(2H, m), 9.25 (1H, s)

(+) APCI-MASS (m/z): 328 (M+H)⁺

EXAMPLE 147

A mixture of(2S)-1-[N-benzyl-N-(2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol(400 mg) and 10% palladium on activated carbon (50% wet, 100 mg) inmethanol (10 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 3 hours and filtered. Thefiltrate was evaporated in vacuo and treated with 4N hydrogen chloridein ethyl acetate to afford(2S)-1-[2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanolhydrochloride (282 mg).

(+) APCI-MASS (m/z): 372 (M+H)⁺

EXAMPLE 148

A mixture of(2S)-1-[N-benzyl-N-(1,4-dimethoxy-5,6,8,9-tetrahydro-5H-benzocyclohepten-7-yl)amino]-3-phenoxy-2-propanol (70 mg) and 10% palladium on activatedcarbon (50% wet, 10 mg) in methanol (10 ml) was stirred at roomtemperature in the presence of hydrogen at an atmospheric pressure for 3hours and filtered. The filtrate was evaporated in vacuo and treatedwith 4N hydrogen chloride in ethyl acetate to afford(2S)-1-[1,4-dimethoxy-5,6,8,9-tetrahydro-5H-benzocyclohepten-7-yl)amino]-3-phenoxy-2-propanolhydrochloride (446 mg).

(+) APCI-MASS (m/z): 408 (M+H)⁺

EXAMPLE 149

A mixture of(2S)-1-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)amino]-3-phenoxy-2-propanol (750 mg) and 10% palladium on activatedcarbon (50% wet, 200 mg) in methanol (10 ml) was stirred at roomtemperature in the presence of hydrogen at an atmospheric pressure for 3hours and filtered. The filtrate was evaporated in vacuo and treatedwith 4N hydrogen chloride in ethyl acetate to afford(2S)-1-[3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)amino]-3-phenoxy-2-propanolhydrochloride (100 mg).

(+) APCI-MASS (m/z): 342 (M+H)⁺

EXAMPLE 150

To a solution of2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid (100 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (61 mg) and1-hydroxybenzotriazole (33 mg) in dichloromethane (10 ml) was added5-aminotetrazole monohydrate (19.3 mg). The resulting mixture wasstirred at room temperature for 18 hours and extracted with ethylacetate. The extract was washed with brine, dried over magnesium sulfateand evaporated in vacuo. The residue was chromatographed (hexane-ethylacetate) over silica gel and treated with 4N hydrogen chloride in ethylacetate to afford2-[8-[(2S)-2-hydroxy-3-phenoxypropyl)amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-2-(tetrazol-5-yl)acetamide(50 mg).

NMR (DMSO-d₆, δ): 1.60-2.10 (3H, m), 2.20-2.30 (1H, m), 2.60-3.60 (7H,m), 3.80-4.30 (2H, m), 4.71 (1H, s), 4.85 (1H, s), 6.60-7.40 (8H, m)

EXAMPLE 151

To a solution of guanidine hydrochloride (463 mg) inN,N-dimethylformamide (20 ml) was added 28% sodium ethoxide (0.22 ml)under ice-cooling, and the mixture was stirred at room temperature for 5minutes. To the resulting mixture was added2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid ethyl ester (400 mg). After being stirred at room temperature for 2hours, the precipitates were collected by filtration and treated with 4Nhydrogen chloride in ethyl acetate to affordN-[2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetyl]guanidinehydrochloride (243 mg).

(+) APCI-MASS (m/z): 427 (M+H)⁺

EXAMPLE 152

A mixture ofN-[8-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethyl]urea(160 mg) and 10% palladium on activated carbon (50% wet, 50 mg) inmethanol (10 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 3 hours and filtered. Thefiltrate was evaporated in vacuo and treated with 4N hydrogen chloridein ethyl acetate to affordN-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethyl]ureahydrochloride (100 mg).

(+) APCI-MASS (m/z): 384 (M+H)⁺

EXAMPLE 153

A mixture of1-[8-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethyl]-3-butylurea(105 mg) and 10% palladium on activated carbon (50% wet, 50 mg) inmethanol (10 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 3 hours and filtered. Thefiltrate was evaporated in vacuo and treated with 4N hydrogen chloridein ethyl acetate to afford1-butyl-3-[8-(2S)-2-hydroxy-3-phenoxypropyl)amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethyl]ureahydrochloride (80 mg).

(+) APCI-MASS (m/z): 440 (M+H)⁺

EXAMPLE 154

A mixture of3-[[8-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethyl]amino]propionicacid tert-butyl ester (100 mg) and 10% palladium on activated carbon(50% wet, 10 mg) in methanol (10 ml) was stirred at room temperature inthe presence of hydrogen at an atmospheric pressure for 3 hours andfiltered. The filtrate was evaporated in vacuo and treated with 4Nhydrogen chloride in ethyl acetate to afford3-[[8-[(2S)-2-hydroxy-3-phenoxypropylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethyl]amino]propionicacid dihydrochloride (80 mg).

NMR (DMSO-d₆, δ): 1.10-1.40 (1H, m), 1.70-2.10 (3H, m), 2.15-3.30 (13H,m), 3.95-4.25 (3H, m), 6.80-7.40 (8H, m), 8.63 (1H, br s)

EXAMPLE 155

A mixture of2-[8-[N-benzyl-N-[(2S)-2-hydroxy-3-[4-benzyloxy-3-methanesulfonylamino]phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-butylacetamide(160 mg) and 10% palladium on activated carbon (50% wet, 30 mg) inmethanol (10 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 3 hours and filtered. Thefiltrate was evaporated in vacuo and treated with 4N hydrogen chloridein ethyl acetate to affordN-butyl-2-[8-[[(2S)-2-hydroxy-3-[4-hydroxy-3-methanesulfonylamino]phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamidehydrochloride (446 mg).

NMR (DMSO-d₆, δ) 0.85 (3H, t, J=7.1 Hz), 1.20-1.50 (5H, m), 1.60-2.10(2H, m), 2.22-2.30 (1H, m), 2.70-2.80 (1H, m), 2.94 (3H, s), 3.05-3.30(7H, m), 3.90 (2H, d, J=4.5 Hz), 4.10-4.25 (1H, m), 4.41 (2H, s),6.60-6.80 (2H, m), 6.85-6.95 (3H, m), 7.05 (1H, d, J=8.2 Hz), 8.04 (1H,br s)

(+) APCI-MASS (m/z): 480 (M+H)⁺

EXAMPLE 156

A mixture of(2S)-1-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-(4-benzyloxy-3-methanesulfonylamino)phenoxy-2-propanol(750 mg) and 10% palladium on activated carbon (50% wet, 200 mg) inmethanol (10 ml) was stirred at room temperature in the presence ofhydrogen at an atmospheric pressure for 3 hours and filtered. Thefiltrate was evaporated in vacuo and treated with 4N hydrogen chloridein ethyl acetate to afford(2S)-3-[3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]amino-1-(4-hydroxy-3-methanesulfonylamino)phenoxy-2-propanolhydrochloride (446 mg).

(+) APCI-MASS (m/z): 342 (M+H)⁺

EXAMPLE 157

To a solution of2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid (200 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (122 mg)and 1-hydroxyenzotriazole hydrate (66 mg) in dichloromethane (20 ml) wasadded dimethylamine hydrochloride (38.4 mg), and the mixture was stirredat room temperature for 18 hours. The resulting mixture was diluted withethyl acetate. The organic layer was washed with brine, dried overmagnesium sulfate and evaporated in vacuo. The residue waschromatographed (hexane-ethyl acetate) over silica gel and treated with4N hydrogen chloride in ethyl acetate to afford2-[8-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N,N-dimethylacetamide(100 mg).

NMR (DMSO-d₆, δ): 1.10-1.40 (1H, m), 1.60-2.10 (2H, m), 2.20-2.30 (1H,m), 2.55-3.30 (13H, m), 3.90-4.30 (3H, m), 4.70 (2H, s), 6.89-7.35 (8H,m)

(+) APCI-MASS (m/z): 413 (M+H)⁺

EXAMPLE 158 TO EXAMPLE 201 Coupling of2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticAcid with n Different Type of Amines

To a solution of2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid (Starting compound) (n×0.01 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (n×0.015 mmol) and1-hydroxybenzotriazole (n×0.012 mmol) in N,N′-dimethylformamide (n×0.1ml) was added 1M N,N-dimethylformamide solution of an amine (0.012 mmol)[n different type of amines] and stirred at room temperature for 2hours.

To each reaction mixture was added 5% sodium hydrogencarbonate solution(0.40 ml), following by extraction with ethyl acetate (0.35 ml). Theresultant aqueous layer was further extracted with ethyl acetate (0.2ml). The combined organic layer was washed with water (0.30 ml). Thenthe resultant aqueous layer was additionally extracted with ethylacetate (0.2 ml×2). The combined organic layer was concentrated bynitrogen flow and treated with 4N hydrogen chloride in ethyl acetate andconcentrated by nitrogen flow. The resultant residue was dissolved indimethylsulfoxide (1.0 ml) to give a ca. 1.0×10⁻²M dimethylsulfoxidesolution of the object compound which was subjected to analysis by massspectrum.

The formula

of the Object compounds and their spectrums in the following Examples158 to Example 201 in Table 1.

Example No.

MALDI-MS (m/z) 158

457 (M + H)⁺ 159

455 (M + H)⁺ 160

443 (M + H)⁺ 161

485 (M + H)⁺ 162

443 (M + H)⁺ 163

498 (M + H)⁺ 164

467 (M + H)⁺ 165

543 (M + H)⁺ 166

498 (M + H)⁺ 167

490 (M + H)⁺ 168

476 (M + H)⁺ 169

493 (M + H)⁺ 170

517 (M + H)⁺ 171

558 (M + H)⁺ 172

573 (M + H)⁺ 173

517 (M + H)⁺ 174

529 (M + H)⁺ 175

506 (M + H)⁺ 176

479 (M + H)⁺ 177

532 (M + H)⁺ 178

620 (M + H)⁺ 179

565 (M + H)⁺ 180

680 (M + H)⁺ 181

623 (M + H)⁺ 182

489 (M + H)⁺ 183

565 (M + H)⁺ 184

542 (M + H)⁺ 185

504 (M + H)⁺ 186

475 (M + H)⁺ 187

491 (M + H)⁺ 188

495 (M + H)⁺ 189

468 (M + H)⁺ 190

487 (M + H)⁺ 191

527 (M + H)⁺ 192

455 (M + H)⁺ 193

455 (M + H)⁺ 194

469 (M + H)⁺ 195

483 (M + H)⁺ 196

479 (M + H)⁺ 197

504 (M + H)⁺ 198

479 (M + H)⁺ 199

551 (M + H)⁺ 200

503 (M + H)⁺ 201

481 (M + H)⁺

EXAMPLE 202

Under nitrogen, a solution of2-(8-amino-6,7,8,9-tetrahydro-5H-bnzocyclohepten-2-yloxy)-N,N-dimethylacetamide(129 mg),N-[2-benzyloxy-5-[(1R)-2-iodo-1-(triethylsilyloxy)ethyl]phenyl]methanesulfonamide(280 mg) and N,N-diisopropylethylamine (0.34 ml) in1,3-dimethyl-2-imidazolidinone (5 ml) was stirred at 110° C. for 42hours. The resulting mixture was poured into saturated aqueous sodiumhydrogencarbonate and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate andevaporated in vacuo. To the residue in ethyl acetate (4 ml) was added 4Nhydrogen chloride in ethyl acetate (1 ml), and the mixture was stirredat room temperature for 1.5 hours. After evaporation, the residue wasdissolved into a mixture of saturated aqueous sodium hydrogencarbonateand ethyl acetate, followed by separation. The organic layer was washedwith brine, dried over anhydrous magnesium sulfate, and evaporated invacuo. The residue was purified by column chromatography on silica gel(chloroform:methanol=50:1 to 10:1) to give2-[8-[(2R)-2-(4-benzyloxy-3-methanesulfonylamino)phenyl-2-hydroxyethylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N,N-dimethylacetamide(145 mg).

NMR (CHCl₃, δ): 1.4-2.1 (4H, m), 2.55-3.15 (7H, m), 2.91 (3H, s), 2.96(3H, m), 3.08 (3H, m), 4.45-4.7 (3H, m), 5.10 (2H, s), 6.65-6.8 (2H, m),6.9-7.0 (2H, m), 7.1-7.2 (1H, m), 7.35-7.55 (6H, m)

(+) APCI-MASS (m/z): 582 (M+H)⁺

The following compound was obtained according to a similar manner tothat of Example 202.

EXAMPLE 203

2-(8-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylaminophenyl)ethylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N,N-dimethylacetamidehydrochloride

NMR (DMSO-d₆, δ): 1.1-1.4 (1H, m), 1.7-2.05 (2H, m), 2.2-2.4 (1H, m),2.55-3.2 (7H, m), 2.83 (3H, s), 2.95 (3H, s), 2.99 (3H, s), 4.73 (2H,s), 4.8-4.95 (1H, m), 6.67 (1H, dd, J=2.2 and 8.2 Hz), 6.75-6.9 (1H, m),6.9-7.4 (4H, m)

(+) APCI-MASS (m/z): 492 (M−HCl+H)⁺

EXAMPLE 204

Under nitrogen, to a solution ofN-[3-[(1S)-2-amino-1-hydroxyethyl]-4-fluorophenyl]methanesulfonamide(200 mg) and 3-methoxy-6,7,8,9-tetrahydrobenzocyclohepten-6-one (146 mg)in tetrahydrofuran (10 ml) was added sodium triacetoxyborohydride (257mg) at room temperature, and the mixture was stirred at the sametemperature for 24 hours. The resulting mixture was poured intosaturated aqueous sodium bicarbonate solution and extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was treated with 4Nhydrogen chloride in ethyl acetate to affordN-[4-fluoro-3-[(1S)-1-hydroxy-2-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)ethyl]phenyl]-methanesulfonamidehydrochloride (304 mg).

(+) APCI-MASS (m/z): 423 (M+H)⁺

EXAMPLE 205

Under nitrogen, a solution of3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamine (720 mg),N-[2-benzyloxy-5-[(1R)-2-iodo-1-(triethylsilyloxy)ethyl]phenyl]-methanesulfonamide(2.1 g) and N,N-diisopropylethylamine (2.6 ml) in N,N-dimethylacetamide(10 ml) was stirred at 110° C. for 96 hours. The resulting mixture waspoured into aqueous 10% sodium hydrogensulfite and extracted with ethylacetate. The organic layer was successively washed with saturatedaqueous sodium hydrogencarbonate and brine, dried over anhydrous sodiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel (chloroform:methanol=40:1 to 20:1) to giveN-[2-benzyloxy-5-[(1R)-1-hydroxy-2-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)ethyl]phenyl]methanesulfonamide(381 mg).

NMR (CDCl₃, δ) 1.4-2.1 (5H, m), 2.5-3.1 (7H, m), 2.90 (3H, s), 3.77 (3H,s), 4.5-4.6 (1H, m), 5.10 (2H, s), 6.6-6.75 (2H, m), 6.97 (1H, d, J=8.5Hz), 6.99 (1H, d, J=8.0 Hz), 7.1-7.2 (1H, m), 7.3-7.5 (5H, m), 7.50 (1H,d, J=1.8 Hz)

(+) APCI-MASS (m/z): 511 (M+H)⁺

The following compound was obtained according to a similar manner tothat of Example 132.

EXAMPLE 206

N-[2-Hydroxy-5-(1R)-1-hydroxy-2-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)ethyl]phenyl]methanesulfonamidehydrochloride

NMR (DMSO-d₆, δ): 1.05-1.4 (1H, m), 1.7-2.1 (2H, m), 2.2-2.4 (1H, m),2.6-2.8 (2H, m), 2.9-3.3 (5H, m), 2.95 (3H, s), 3.71 (3H, s), 4.8-4.95(1H, m), 6.65-7.2 (5H, m), 7.28 (1H, s)

(+) APCI-MASS (m/z): 421 (M−HCl+H)⁺

EXAMPLE 207

Under nitrogen, a solution of2-(8-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)acetic acidtert-butyl ester (321 mg),N-[2-benzyloxy-5-[(1R)-2-iodo-1-(triethylsilyloxy)ethyl]phenyl]methanesulfonamide(620 mg) and N,N-diisopropylethylamine (0.77 ml) in1,3-dimethyl-2-imidazolidinone (5 ml) was stirred at 110° C. for 24hours. The resulting mixture was poured into saturated aqueous sodiumhydrogencarbonate and extracted with ethyl acetate. The organic layerwas successively washed with water twice and brine, dried over anhydroussodium sulfate and evaporated in vacuo. Under nitrogen, to the residuein tetrahydrofuran (10 ml) was added 1M tetra-n-butylammonium fluoridein tetrahydrofuran (2 ml) at 5° C., and the mixture was stirred at roomtemperature for 1 hour. The resulting mixture was poured into saturatedaqueous sodium hydrogencarbonate and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel (chloroform:methanol=50:1) to give2-[8-[(2R)-2-(4-benzyloxy-3-methanesulfonylamino)phenyl-2-hydroxyethylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid tert-butyl ester (366 mg).

(+) APCI-MASS (m/z): 611 (M+H)⁺

EXAMPLE 208

A mixture of2-[8-[(2R)-2-(4-benzyloxy-3-methanesulfonylaminophenyl)-2-hydroxyethylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid tert-butyl ester (353 mg) and 10% palladium on activated carbon(50% wet, 100 mg) in methanol (5 ml) was stirred at room temperature inthe presence of hydrogen at an atmospheric pressure for 3.5 hours. Afterfiltration, the filtrate was evaporated in vacuo. The residue waspurified by column chromatography on silica gel(chloroform:methanol=10:1 to 5:1) to give2-[8-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylaminophenyl)ethylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid tert-butyl ester (268 mg).

(+) APCI-MASS (m/z): 521 (M+H)⁺

EXAMPLE 209

Under nitrogen, to a solution of2-[8-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylaminophenyl)ethylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid tert-butyl ester (257 mg) in dichloromethane (5 ml) was addedtrifluoroacetic acid (1 ml) at 5° C., and the mixture was stirred atroom temperature for 3 hours. The resulting mixture was evaporated invacuo. The residue was treated with 4N hydrogen chloride in 1,4-dioxaneto give2-[8-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylaminophenyl)ethylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]aceticacid hydrochloride (247 mg).

(+) APCI-MASS (m/z): 465 (M−HCl+H)⁺

The following compound was obtained according to a similar manner tothat of Example 205.

EXAMPLE 210

2-[8-[(2R)-2-(4-Benzyloxy-3-methanesulfonylaminophenyl)-2-hydroxyethylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-phenylacetamide

NMR (CDCl₃, δ): 1.4-2.1 (4H, m), 2.5-3.1 (7H, m), 2.90 (3H, s), 4.5-4.65(1H, m), 4.58 (2H, s), 5.09 (2H, s), 6.71 (1H, dd, J=2.6 and 8.1 Hz),6.81 (1H, d, J=2.6 Hz), 6.9-7.2 (4H, m), 7.25-7.65 (10H, m), 8.32 (1H,br s)

(+) APCI-MASS (m/z): 630 (M+H)⁺

The following compound was obtained according to a similar manner tothat of Example 79.

EXAMPLE 211

2-[8-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylaminophenyl)ethylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-phenylacetamidehydrochloride

NMR (DMSO-d₆, δ): 1.1 (4H, m), 2.6-2.8 (2H, m), 2.9-3.7 (8H, m), 4.67(2H, s), 4.8-4.9 (1H, m), 6.7-7.4 (9H, m), 7.65 (2H, d, J=7.8 Hz)

(+) APCI-MASS (m/z): 540 (M−HCl+H)⁺

EXAMPLE 212

Under nitrogen, a solution of 3-oxiranylpyridine (1.9 g) andN-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(3.3 9) in ethanol (15 ml) was refluxed for 5 hours. After removal ofethanol in vacuo, the residue was dissolved into a mixture of aqueoussodium hydrogencarbonate and ethyl acetate. After separation, theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel (chloroform:methanol=20:1) to give2-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-1-(pyridin-3-yl)ethanol (520 mg).

(+) APCI-MASS (m/z): 403 (M+H)⁺

The following compound was obtained according to a similar manner tothat of Example 132.

EXAMPLE 213

2-(3-Methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-1-(pyridin-3-yl)ethanoldihydrochloride

(+) APCI-MASS (m/z): 313 (M−2HCl+H)⁺

EXAMPLE 214

A mixture ofN-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine(0.30 g) and (R)-3-chlorophenyl oxirane (0.18 g) in ethanol (0.6 ml) wasrefluxed overnight. The reaction mixture was evaporated in vacuo, andthe residue was purified by column chromatography on silica gel elutingwith a mixture of hexane and ethyl acetate (5:1). The product (0.43 g)was treated with 4N hydrogen chloride in ethyl acetate and powdered fromdiisopropyl ether to afford(1R)-2-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-1-(3-chlorophenyl)ethanol(0.40 g).

NMR (DMSO-d₆, δ): 1.10-1.25 (1H, m), 1.91-2.18 (2H, m), 2.42-2.80 (3H,m), 2.98-3.62 (5H, m), 3.74 (3H, s), 4.43-4.73 (3H, m), 6.36-6.46 (1H,br), 6.68 (1H, d, J=7.9 Hz), 7.01 (1H, d, J=8.3 Hz), 7.11-7.19 (1H, m),7.29-7.55 (7H, m), 7.68-7.90 (2H, m), 10.00-10.15 (1F, br)

(+) APCI-MASS (m/z): 436, 438 (M+H)⁺

EXAMPLE 215

A mixture of(1R)-2-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-1-(3-chlorophenyl)ethanolhydrochloride (0.20 g), chlorobenzene (0.86 ml) and 10% palladium oncarbon (0.01 g) in methanol (4 ml) was stirred at room temperature underhydrogen atmosphere for 1.5 hours. The catalyst was filtered off andwashed with methanol. The filtrate was evaporated in vacuo, and theresidue was powdered from diisopropyl ether to afford(1R)-2-[(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-1-(3-chlorophenyl)ethanolhydrochloride (0.14 g)

IR (KBr): 3328, 2933, 1608, 1502, 1444, 1261 cm⁻¹

NMR (DMSO-d₆, δ): 1.17-1.35 (1H, m), 1.78-2.08 (2H, m), 2.22-2.37 (1H,m), 2.62-2.72 (2H, m), 2.98-3.30 (5H, m), 3.71 (3H, s), 4.95-5.05 (1H,m), 6.33 (1H, d, J=4.0 Hz), 6.70 (1H, d, J=8.2 Hz), 6.83 (1H, dd,J=12.3, 2.5 Hz), 7.04 (1H, d, J=8.2 Hz), 7.30-7.43 (3H, m), 7.52 (1H,s), 8.72 (1H, br s), 9.00 (1H, br s)

(+) APCI-MASS (m/z): 346, 348 (M−HCl+H)⁺

The following compound was obtained according to a similar manner tothat of Example 214.

EXAMPLE 216

2-[8-[N-Benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-N-phenylacetamidehydrochloride

NMR (DMSO-d₆, δ) 1.05-1.30 (1H, m), 1.91-2.15 (2H, m), 2.40-2.50 (1H,m), 2.62-2.75 (2H, m), 3.02-3.60 (6H, m), 4.45-4.72 (4H, m), 6.34-6.45(1H, br), 6.75 (1H, d, J=8.2 Hz), 7.01-7.20 (3H, m), 7.27-7.48 (9H, m),7.62-7.68 (2H, m), 7.70-7.90 (2H, m), 9.83 (1H, br s), 10.19 (1H, d,J=7.8 Hz)

(+) APCI-MASS (m/z): 555, 557 (M+H)⁺

The following compound was obtained according to a similar manner tothat of Example 215.

EXAMPLE 217

2-[8-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-phenylacetamide

IR (KBr) 3394, 2933, 1679, 1600, 1540, 1502, 1442, 1253 cm⁻¹

NMR (DMSO-d₆, δ): 1.16-1.30 (1H, m), 1.72-2.05 (2H, m), 2.22-2.38 (1H,m), 2.60-2.70 (2H, m), 3.00-3.35 (5H, m), 4.66 (2H, d, J=2.4 Hz),4.95-5.04 (1H, m), 6.33 (1H, br s), 6.77 (1H, d, J=8.4 Hz), 6.92 (1H, d,J=12.3 Hz), 7.04-7.10 (2H, m), 7.27-7.41 (5H, m), 7.52 (1H, s),7.62-7.66 (2H, m), 8.75 (1H, br s), 9.12 (1H, br s), 10.16 (1H, d, J=6.1Hz)

(+) ESI-MASS (m/z): 465, 467 (M+H)⁺

EXAMPLE 218

According to a similar manner to that of Test 1 described before, theeffects of the present compounds on the intravesical pressure wereevaluated. Particularly, ED50(μg/kg) of the compound prepared in Example155 was 10.8.

What is claimed is:
 1. A compound of the general formula (I):

wherein R¹ is aryl which may have one or more suitable substituent(s),heterocyclic group or cyclo(lower)alkyl, R² is hydrogen or aminoprotective group, R³ and R⁴ are independently hydrogen, halogen,hydroxy, amino, nitro, carboxy, protected carboxy, aryl, lower alkyl,hydroxy(lower)alkyl, amino(lower)alkyl, acyloxy(lower)alkyl,acylamino(lower)alkyl, lower alkylamino(lower)alkyl which may have oneor more suitable substituent(s), mono or di-(lower)alkylamino,acylamino, acyl group, lower alkoxy, halo(lower)alkoxy, loweralkenyloxy, lower alkoxy(lower)alkoxy, aryloxy, cyclo(lower)alkyloxy,heterocyclicoxy, ar(lower)alkyloxy, acyloxy or acyl(lower)alkoxy, R⁵ ishydrogen, lower alkyl, or aryl, A is lower alkylene which may have oneor more suitable substituent(s) or lower alkenylene, X is O, S, SO, SO₂or NH, and m is an integer of 0 or 1, or a salt thereof, wherein when R¹is naphthyl and R⁵ is H, then X is not O.
 2. The compound of claim 1,wherein R¹ is phenyl which may have one or more suitable substituent(s),R² is hydrogen, R³ is acyl(lower)alkoxy, lower alkoxy, protectedcarboxy, hydroxy or acyloxy, R⁴ is hydrogen, R⁵ is hydrogen, A is loweralkylene, X is O, and m is an integer of
 1. 3. The compound of claim 2,wherein R¹ is phenyl which may have 1 or 2 suitable substituent(s)selected from the group consisting of hydroxy and loweralkylsulfonylamino, R³ is lower alkylcarbamoyl(lower)alkoxy,heterocycliccarbamoyl(lower)alkoxy, heterocycliccarbonyl(lower)alkoxy,N-lower alkyl-lower alkylcarbamoyl(lower)alkoxy, hydroxy, lower alkoxy,protected carboxy, arylcarbamoyl(lower)alkoxy which may have loweralkoxy or di(lower)alkylamino, di-lower alkylsulfamoyloxy, N-loweralkylheterocyclic(lower)alkylcarbamoyl(lower)alkoxy, N-lower alkyl-loweralkylcarbamoyl(lower)alkoxy or N-loweralkyl-cyclo(lower)alkylcarbamoyl(lower)alkoxy.
 4. The compound of claim3, wherein R¹ is phenyl which may have hydroxy and methylsulfonylamino,R³ is ethylcarbamoylmethoxy, indolylcarbamoylmethoxy,piperidinocarbonylmethoxy, N-methylbutylcarbamoylmethoxy, hydroxy,butylcarbamoylmethoxy, methoxy, methoxycarbonyl, ethoxy,dimethylsulfamoyloxy, tetrazolylcarbamoylmethoxy,N-methylpyridylethylcarbamoylmethoxy, methoxyphenylcarbamoylmethoxy,thiazolylcarbamoylmethoxy, dihydroindolylcarbonylmethoxy,N-ethylpropylcarbamoylmethoxy, N-methylbutylcarbamoylmethoxy,N-ethylbutylcarbamoylmethoxy, dimethylaminophenylcarbamoylmethoxy orN-methylcyclohexylcarbamoylmethoxy.
 5. A process for preparing acompound of claim 1, or a salt thereof, which comprises, (i) reacting acompound (II) of the formula:

wherein R¹, R⁵, A, X and m are each as defined in claim 1, with acompound (III) of the formula:

wherein R², R³ and R⁴ are each as defined in claim 1, or a salt thereof,to give a compound (I) of the formula:

wherein R¹, R², R³, R⁴, R⁵, A, X and m are each as defined in claim 1,or a salt thereof, or (ii) subjecting a compound (Ia) of the formula:

wherein R¹, R³, R⁴, R⁵, A, X and m are each as defined in claim 1, andR_(a) ² is amino protective group, or a salt thereof, to eliminationreaction of the amino protective group, to give a compound (Ib) of theformula:

wherein R¹, R³, R⁴, R⁵, A, X and m are each as defined in claim 1, or asalt thereof.
 6. A pharmaceutical composition which comprises a compoundof claim 1 or a pharmaceutically acceptable salt thereof in admixturewith a pharmaceutically acceptable carrier or excipient.
 7. A method formaking a pharmaceutical composition or a medicament comprising admixinga compound of claim 1 or a pharmaceutically acceptable salt thereof witha pharmaceutically acceptable carrier or excipient.
 8. A compound ofclaim 1 or a pharmaceutically acceptable salt thereof compounded as atablet, pellet, troche, capsule, suppository, cream, ointment, aerosol,powder for insufflation, solution, emulsion, or suspension.
 9. A methodfor the prophylactic and/or the therapeutic treatment of pollakiuria orurinary incontinence which comprises administering an effective amountof a compound of claim 1 or a pharmaceutically acceptable salt thereofto a subject in need thereof.
 10. A method for agonizing a β₃ adrenergicreceptor comprising contacting said receptor with a compound of claim 1.11. A method for inducing gut-selective sympathomimetic activitycomprising administering an effective amount of a compound of claim 1 toa subject in need thereof.
 12. A method for the prophylactic and/or thetherapeutic treatment of a gastrointestinal disorder comprisingadministering an effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof to a subject in need thereof.13. A method for the prophylactic and/or the therapeutic treatment of anulcer or pancreatitis comprising administering an effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof to asubject in need thereof.
 14. A method for inducing lypolysis comprisingadministering an effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof to a subject in need thereof.